Quinazoline derivatives and pharmaceutical compositions containing them

ABSTRACT

The invention relates to quinazoline derivatives of formula (1)  
                 
 
wherein m is an integer from 1 to 2; R 1  represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6  (wherein R 5  and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2  represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X 1  represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10  and R 11  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); R 4  represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

The present invention relates to quinazoline derivatives, processes fortheir preparation, pharmaceutical compositions containing them as activeingredient, methods for the treatment of disease states associated withangiogenesis and/or increased vascular permeability, to their use asmedicaments and to their use in the manufacture of medicaments for usein the production of antiangiogenic and/or vascular permeabilityreducing effects in warm-blooded animals such as humans.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman,1995, Nature Medicine 1: 27-31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139-155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841-844).

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signalling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefms-like tyrosine kinase receptor, Flt or Flt1, the kinase insertdomain-containing receptor, KDR (also referred to as Flk-1), and anotherfins-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fltand KDR, have been shown to bind VEGF with high affinity (De Vries etal, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys.Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptorsexpressed in heterologous cells has been associated with changes in thetyrosine phosphorylation status of cellular proteins and calcium fluxes.

European Patent Publication No. 0326330 discloses certain quinoline,quinazoline and cinnoline plant fungicides. Certain of these plantfungicides are also stated to possess insecticidal and miticidalactivity. There is however no disclosure or any suggestion that any ofthe compounds disclosed may be used for any purpose in animals such ashumans. In particular, the European Patent Publication contains noteaching whatsoever concerning angiogenesis and/or increased vascularpermeability mediated by growth factors such as VEGF.

European Patent Publication No. 0566226 discloses anilinoquinazolineswhich have activity against epidermal growth factor (EGF) receptortyrosine kinase. EP 0566226 contains no teaching whatsoever concerningangiogenesis and/or increased vascular permeability mediated by growthfactors such as VEGF. Moreover compounds of EP 0566226 which have beentested do not show significant activity against VEGF receptor tyrosinekinase.

The present invention is based on the surprising discovery that certainquinazolines inhibit the effects of VEGF, a property of value in thetreatment of disease states associated with angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation.Compounds of the present invention possess good activity against VEGFreceptor tyrosine kinase whilst possessing some activity against EGFreceptor tyrosine kinase. Furthermore, some compounds of the presentinvention, possess substantially higher potency against VEGF receptortyrosine kinase than against EGF receptor tyrosine kinase or FGF R1receptor tyrosine kinase. Thus certain compounds of the invention whichhave been tested possess activity against VEGF receptor tyrosine kinasesuch that they may be used in an amount sufficient to inhibit VEGFreceptor tyrosine kinase whilst demonstrating no significant activityagainst EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase.While we do not wish to be bound by theoretical considerations suchcompounds may for example be of interest in treating tumours which areassociated with VEGF, especially those tumours which are dependent onVEGF for their growth.

Other compounds of the invention possess good activity against both VEGFand EGF receptor tyrosine kinases. Indeed certain compounds possesssubstantially equivalent activities against VEGF and EGF receptortyrosine kinases. It is believed that these compounds may be of interestin treating tumour states associated with both VEGF and EGF, especiallywhere a patient is suffering from a condition in which tumours arepresent which are dependent on both VEGF and EGF for their growth.

According to one aspect of the present invention there is provided aquinazoline derivative of the formula I:

[wherein:

-   m is an integer from 1 to 2;-   R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl,    cyano, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, or —NR⁵R⁶ (wherein R⁵    and R⁶, which may be the same or different, each represents hydrogen    or C₁₋₃alkyl);-   R² represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro:-   R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,    C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino or nitro;-   X¹ represents —O—, —CH₂—, —S—, —SO—, —SO₂—, —NR⁷CO—, —CONR⁸—,    —SO₂NR⁹—, —NR¹⁰SO₂— or —NR¹¹— (wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ each    independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   R⁴ is selected from one of the following eight groups:-   1) C₁₋₅alkylR¹² (wherein R¹² is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    C₁₋₅alkyl through a carbon atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) or    C₁₋₅alkylR¹³ (wherein R¹³ is a group selected from pyrrolidin-1-yl,    imidazolidin-1-yl and thiomorpholino, which group may bear one or    two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   2) C₂₋₅alkenylR¹⁴ (wherein R¹⁴ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear one    or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   3) C₂₋₅alkynylR¹⁵ (wherein R¹⁵ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear one    or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   4) C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶ (wherein X² and X³ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR¹⁷CO—,    —CONR¹⁸—, —SO₂NR¹⁹—, —NR²⁰SO₂— or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰    and R²¹ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents hydrogen or C₁₋₃alkyl) with    the proviso that X¹ cannot be —CH₂— when R⁴ is    C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶;-   5) C₁₋₅alkylX⁴COR²² (wherein X⁴ represents —O— or —NR²³— (wherein    R²³ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²²    represents —NR²⁴R²⁵ or —OR²⁶ (wherein R²⁴, R²⁵ and R²⁶ which may be    the same or different each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl));-   6) C₁₋₅alkylX⁵R²⁷ (wherein X⁵ represents —O—, —S—, —SO—, —SO₂—,    —OCO—, —NR²⁸CO—, —CONR²⁹—, —SO₂NR³⁰—, —NR³¹SO₂ or —NR³²— (wherein    R²⁸, R²⁹, R³⁰, R³¹ and R³² each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) or X⁵ is carbonyl, and R²⁷    represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which cyclopentyl, cyclohexyl or    heterocyclic group may bear one or two substituents selected from    oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy,    and additional possible substituents are carbamoyl,    C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and    C₁₋₄alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when    R²⁷ is C₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³¹— or —NR³¹SO₂— and    X¹ is not —CH₂—);-   7) C₁₋₃alkoxyC₂₋₄alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and-   8) C₁₋₃alkoxyC₂₋₄alkyl or C₁₋₄alkyl provided that X¹ is —O—; and    additionally R⁴ may be selected from the following five groups:-   9) C₁₋₅alkylX⁶C₁₋₅alkylR³³ (wherein X⁶ represents —O—, —S—, —SO—,    —SO₂—, —NR³⁴CO—, —CONR³⁵—, —SO₂NR³⁶—, —NR³⁷SO₂— or —NR³⁸— (wherein    R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ represents cyclopentyl,    cyclohexyl or a 5 or 6 membered saturated heterocyclic group with    one or two heteroatoms, selected independently from O, S and N,    which cyclopentyl, cyclohexyl or heterocyclic group may bear one or    two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   10) R³⁹ (wherein R³⁹ is a group selected from pyrrolidin-3-yl,    piperidin-3-yl and piperidin-4-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   11) C₁₋₅alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least    one substituent selected from C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,    C₁₋₄hydroxyalkyl and —CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each    independently represents hydrogen or C₁₋₄alkyl);-   12) C₁₋₅alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or    two substituents selected from oxo, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,    carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl,    C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) with the proviso that when R⁴    is C₁₋₅alkylR⁴³, X¹ is —S—, —SO—, —SO₂—, —SO₂NR⁹— or —NR¹⁰SO₂—; and-   13) C₁₋₅alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one    and optionally two substituents selected from oxo, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   with the further proviso that when R⁴ is selected from group 8) R¹    and/or R² is/are nitro or at least one R³ is C₁₋₃alkanoyloxy;]    and salts thereof.

Preferably m is 2.

R¹ is advantageously hydrogen, hydroxy, cyano, nitro, trifluoromethyl,C₁₋₃alkyl, C₁₋₃alkoxy or amino.

R¹ is preferably hydrogen, hydroxy, cyano, nitro, trifluoromethyl,methyl, ethyl, methoxy or ethoxy, more preferably hydrogen, methyl ormethoxy, most preferably hydrogen or methoxy, but especially methoxy.

R² is preferably hydrogen, fluoro, amino or nitro, but especiallyhydrogen.

In one embodiment of the present invention R³ represents hydroxy,halogeno, C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, cyano, amino or nitro.

Advantageously in another embodiment of the present invention one R³substituent is meta-hydroxy and the other one is selected from halogenoand methyl.

In another embodiment of the invention the phenyl group bearing (R³)_(m)is preferably of the formula II:

wherein:

-   R^(a) represents hydrogen, methyl, fluoro or chloro, preferably    hydrogen or fluoro;-   R^(b) represents hydrogen, methyl, methoxy, bromo, fluoro or chloro,    especially hydrogen, methyl or chloro;-   R^(c) represents hydrogen or hydroxy;-   R^(d) represents hydrogen, fluoro or chloro, especially hydrogen or    fluoro.

In a particular aspect of the present invention, the phenyl groupbearing (R³), is the 3-hydroxy-4-methylphenyl group, the2-fluoro-5-hydroxyphenyl group or the 4-chloro-2-fluorophenyl group, orthe 4-bromo-2-fluorophenyl group, especially the 4-chloro-2-fluorophenylgroup or the 4-bromo-2-fluorophenyl group more especially the4-chloro-2-fluorophenyl group.

Advantageously X¹ represents —O—, —S—, —NR⁷CO—, —NR¹⁰SO₂— or —NR¹¹—(wherein R⁷, R¹⁰ and R¹¹ each independently represents hydrogen,C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹ represents —O—, —S—, —NR⁷CO— or —NR¹⁰SO₂— (wherein R⁷ andR¹⁰ each independently represents hydrogen or C₁₋₂alkyl).

More preferably X¹ represents —O—, —S—, —NR⁷CO— (wherein R⁷ representshydrogen or methyl).

Particularly X¹ represents —O—, or —NHCO—, or —S—, especially —O—, or—S—, more especially —O—.

Conveniently X² and X³ which may be the same or different eachrepresents —O—, —S—, —SO—, —SO₂—, —NR¹⁷CO—, or —NR²¹ — (wherein R¹⁷ andR²¹ each independently represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

Advantageously X² and X³ which may be the same or different eachrepresents —O—, —S—, —SO—, —SO₂— or —NR²¹— (wherein R²¹ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X² and X³ which may be the same or different each represents—O—, —S— or —NR²¹— (wherein R²¹ represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

In a particular aspect of the present invention X³ is —O— and X² is—NR¹⁷CO— (wherein R¹⁷ represents hydrogen, or methyl).

Advantageously X⁴ represents —O— or —NR²³— (wherein R²³ representshydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).

Advantageously X⁵ represents —O—, —S—, —SO—, —SO₂—, —NR²⁸CO—, —NR³¹SO₂—or —NR³²— (wherein R²⁸, R³¹ and R³² each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl) or X⁵ is carbonyl.

Preferably X⁵ represents —O—, —S—, —SO—, —SO₂— or —NR³²— (wherein R³²represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably X⁵ represents —O— or —NR³²— (wherein R³² representshydrogen or C₁₋₂alkyl).

Advantageously X⁶ represents —O—, —S—, —SO—, —SO₂—, —NR³⁴CO—, —NR³⁷SO₂—or —NR³⁸= (wherein R³⁴, R³⁷ and R³⁸ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁶ represents —O—.

Conveniently R⁴ is selected from one of the following eight groups:

-   1) C₁₋₅alkylR¹² (wherein R¹² is a group selected from    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, and    piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,    morpholin-3-yl and piperazin-2-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) or    C₂₋₅alkylR⁴⁵ (wherein R⁴⁵ is a group selected from    imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino, which group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional    possible substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   2) C₃, alkenylR⁴⁶ (wherein R⁴⁶ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    C₃₋₅alkenyl through a carbon atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) or    C₄₋₅alkenylR⁴⁷ (wherein R⁴⁷ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms of which one is N and    the other is selected independently from O, S and N, which    heterocyclic group is linked to C₄₋₅alkenyl through a nitrogen atom    and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl    and C₁₋₄alkoxy, and additional possible substituents are carbamoyl,    C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and    C₁₋₄alkoxycarbonyl);-   3) C₃₋₅alkynylR⁴⁸ (wherein R⁴⁸ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    C₃₋₅alkynyl through a carbon atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, and additional possible    substituents are carbamoyl, C₁₋₄alkylcarbamoyl,    N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) or    C₄₋₅alkynylR⁴⁹ (wherein R⁴⁹ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms of which one is N and    the other is selected independently from O, S and N, which    heterocyclic group is linked to C₄₋₅alkynyl through a nitrogen atom    and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl    and C₁₋₄alkoxy, and additional possible substituents are carbamoyl,    C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and    C₁₋₄alkoxycarbonyl);-   4) C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶ (wherein X² and X³ are as defined    hereinbefore and R¹⁶ represents hydrogen or C₁₋₃alkyl) with the    proviso that X¹ cannot be —CH₂— when R⁴ is    C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶;-   5) C₂₋₃alkylX⁴COR²² (wherein X⁴ is as defined hereinbefore and R²²    represents —NR²⁴R²⁵ or —OR²⁶ (wherein R²⁴, R²⁵ and R²⁶ which may be    the same or different each represents hydrogen, C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   6) C₂₋₄alkylX⁵R²⁷ (wherein X⁵ is as defined hereinbefore and R²⁷    represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which cyclopentyl, cyclohexyl or    heterocyclic group may bear one or two substituents selected from    oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy,    and additional possible substituents are carbamoyl,    C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and    C₁₋₄alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when    R²⁷ is C₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³⁰— or —NR³¹SO₂— and    X¹ is not —CH₂—);-   7) C₁₋₃alkoxyC₂₋₄alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and-   8) C₁₋₃alkoxyC₂₋₄alkyl or C₁₋₄alkyl provided that X¹ is —O—; and    additionally R⁴ may conveniently be selected from the following four    groups:-   9) C₂₋₄alkylX⁶C₂₋₄alkylR³³ (wherein X⁶ is as defined hereinbefore    and R³³ represents a 5 or 6 membered saturated heterocyclic group    with one or two heteroatoms, selected independently from O, S and N,    which heterocyclic group may bear one or two substituents selected    from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,    C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₄alkyl)carbamoyl,    C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl);-   10) C₂₋₄alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least    one substituent selected from C₂₋₃alkanoyl, C₁₋₃alkoxycarbonyl,    C₁₋₃hydroxyalkyl and CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each    independently represents hydrogen or C₁₋₃alkyl));-   11) C₂₋₄alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or    two substituents selected from oxo, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    carbamoyl, C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl,    C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl) with the proviso that when R⁴    is C₂₋₄alkylR⁴³, X¹ is —S—, —SO—, —SO₂—, —SO₂NR⁹— or —NR¹⁰SO₂—; and-   12) C₂₋₄alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one    and optionally two substituents selected from oxo, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl);    with the further proviso that when R⁴ is selected from group 8) R¹    and/or R² is/are nitro or at least one R³ is C₁₋₃alkanoyloxy.

An additional convenient value of R⁴ is C₂₋₃alkylX²methylX³R¹⁶ (whereinX² and X³ are as defined hereinbefore and R¹⁶ represents hydrogen orC₁₋₃alkyl) with the proviso that X¹ cannot be —CH₂— when R⁴ isC₂₋₃alkylX²methylX³R¹⁶.

Advantageously R⁴ is selected from one of the following seven groups:

-   1) C₁₋₄alkylR¹² (wherein R¹² is a group selected from    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, and    piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,    morpholin-3-yl and piperazin-2-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl and C₁₋₃alkoxy, and additional possible    substituents are carbamoyl, C₂₋₄alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₁₋₃alkanoyl and C₁₋₃alkoxycarbonyl) or    C₂₋₄alkylR⁴⁵ (wherein R⁴⁵ is a group selected from    imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy, and additional    possible substituents are carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl);-   2) 1-R⁴⁶prop-1-en-3-yl, 1-R⁴⁶but-2-en-4-yl, 1-R⁴⁶but-1-en-3-yl,    1-R⁴⁶pent-2-en-4-yl or 2-R⁴⁶pent-3-en-5-yl (wherein R⁴⁶ is a 5 or 6    membered saturated heterocyclic group with one or two heteroatoms,    selected independently from O, S and N, which heterocyclic group is    linked to the alkenyl group through a carbon atom and which    heterocyclic group may bear one or two substituents selected from    oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy,    and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl) or 1-R⁴⁷but-2-en-4-yl, 1-R⁴⁷pent-2-en-4-yl or    2-R⁴⁷pent-3-en-5-yl (wherein R⁴⁷ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, of which one is N    and the other is selected independently from O, S and N, which    heterocyclic group is linked to the alkenyl group through a nitrogen    atom and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl    and C₁₋₃alkoxy, and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl);-   3) 1-R⁴⁸prop-1-yn-3-yl, 1-R⁴⁸but-2-yn-4-yl, 1-R⁴⁸but-1-yn-3-yl,    1-R⁴⁸pent-2-yn-4-yl or 2-R⁴⁸pent-3-yn-5-yl (wherein R⁴⁸ is a 5 or 6    membered saturated heterocyclic group with one or two heteroatoms,    selected independently from O, S and N, which heterocyclic group is    linked to the alkynyl group through a carbon atom and which    heterocyclic group may bear one or two substituents selected from    oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy,    and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl) or 1-R⁴⁹but-2-yn-4-yl, 1-R⁴⁹pent-2-yn-4-yl or    2-R⁴⁹pent-3-yn-5-yl (wherein R⁴⁹ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, of which one is N    and the other is selected independently from O, S and N, which    heterocyclic group is linked to the alkynyl group through a nitrogen    atom and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl    and C₁₋₃alkoxy, and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl);-   4) C₂₋₃alky X²C₂₋₃alkylX³R¹⁶ (wherein X² and X³ are as defined    hereinbefore and R¹⁶ represents hydrogen or C₁₋₃alkyl) with the    proviso that X¹ cannot be —CH₂— when R⁴ is    C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶;-   5) C₂₋₃alkylX⁴COR²² (wherein X⁴ is as defined hereinbefore and R²²    represents —NR²⁴R²⁵ or —OR²⁶ (wherein R²⁴, R²⁵ and R²⁶ which may be    the same or different each represents hydrogen, C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   6) C₂₋₃alkylX⁵R²⁷ (wherein X⁵ is as defined hereinbefore and R²⁷    represents a group selected from cyclopentyl, cyclohexyl,    pyrrolidinyl and piperidinyl which group is linked to X⁵ through a    carbon atom and which group may carry one substituent selected from    oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy,    and additional possible substituents are carbamoyl,    C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and    C₁₋₂alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when    R²⁷ is C₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³⁰— or —NR³¹SO₂— and    X¹ is not —CH₂—); and-   7) C₁₋₂alkoxyC₂₋₃alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and additionally R⁴ may advantageously be selected from the    following four groups:-   8) C₂₋₃alkylX⁶C₂₋₃alkylR³³ (wherein X¹ is as defined hereinbefore    and R³³ represents a 5 or 6 membered saturated heterocyclic group    with one or two heteroatoms, selected independently from O, S and N,    which heterocyclic group may bear one or two substituents selected    from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃alkoxy, carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₁₋₃alkanoyl, and C₁₋₃alkoxycarbonyl);-   9) C₂₋₃alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least    one substituent selected from acetyl, C₁₋₂alkoxycarbonyl,    C₁₋₂hydroxyalkyl and CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each    independently represents hydrogen or C₁₋₂alkyl);-   10) C₂₋₃alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or    two substituents selected from oxo, C₁₋₂alkyl, C₁₋₂hydroxyalkyl,    carbamoyl, C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl    and C₁₋₂alkoxycarbonyl) with the proviso that when R⁴ is    C₂₋₃alkylR⁴³, X¹ is —S—, —SO—, —SO₂—, —SO₂NR⁹— or —NR¹⁰SO₂—; and-   11) C₂₋₃alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one    and optionally two substituents selected from oxo, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl).

An additional advantageous value of R⁴ is C₂₋₃alkylX²methylX³R¹⁶(wherein X² and X³ are as defined hereinbefore and R¹⁶ representshydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be —CH₂— when R⁴is C₂₋₃alkylX²methylX³R¹⁶.

Preferably R⁴ is selected from one of the following seven groups:

-   1) C₁₋₃alkylR¹² (wherein R¹² is a group selected from    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl and    piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,    morpholin-3-yl and piperazin-2-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl and C₁₋₃alkoxy, and additional possible    substituents are carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and C₁₋₃alkoxycarbonyl) or    C₂₋₃alkylR⁴⁵ (wherein R⁴⁵ is a group selected from    imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy and additional    possible substituents are carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and C₁₋₃alkoxycarbonyl);-   2) 1-R⁴⁶but-2-en-4-yl (wherein R⁴⁶ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    the alkenyl group through a carbon atom and which heterocyclic group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy, and additional    possible substituents are carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and C₁₋₃alkoxycarbonyl) or    1-R⁴but-2-en-4-yl (wherein R⁴⁷ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, of which one is N    and the other is selected independently from O, S and N, which    heterocyclic group is linked to the alkenyl group through a nitrogen    atom and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl    and C₁₋₃alkoxy, and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and    C₁₋₃alkoxycarbonyl);-   3) 1-R⁴⁸but-2-yn-4-yl (wherein R⁴⁸ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    the alkynyl group through a carbon atom and which heterocyclic group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy, and additional    possible substituents are carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and C₁₋₃alkoxycarbonyl) or    1-R⁴⁹but-2-yn-4-yl (wherein R⁴⁹ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, of which one is N    and the other is selected independently from O, S and N, which    heterocyclic group is linked to the alkynyl group through a nitrogen    atom and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl    and C₁₋₃alkoxy, and additional possible substituents are carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, acetyl and    C₁₋₃alkoxycarbonyl);-   4) C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶ (wherein X² and X³ are as defined    hereinbefore and R¹⁶ represents hydrogen or C₁₋₃alkyl) with the    proviso that X¹ cannot be —CH₂— when R⁴ is    C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶;-   5) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl or 2-(1,3,3-trimethylureido)ethyl,    3-(1,3,3-trimethylureido)propyl, 2-(isopropoxycarbonylamino)ethyl,    3-(isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl,    3-(isobutoxycarbonylamino)propyl, 2-(t-butoxycarbonylamino)ethyl or    3-(t-butoxycarbonylamino)propyl;-   6) C₂₋₃alkylX⁵R²⁷ (wherein X⁵ is as defined hereinbefore and R²⁷ is    a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and    piperidinyl which group is linked to X⁵ through a carbon atom and    which group may carry one substituent selected from oxo, hydroxy,    halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy and additional    possible substituents are carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl or R²⁷ is    C₁₋₂alkyl with the proviso that when R²⁷ is C₁₋₂alkyl, X⁵ is —S—,    —SO—, —SO₂—, —SO₂NR³⁰— or —NR¹¹SO₂— and X¹ is not —CH₂—); and-   7) C₁₋₂alkoxyC₂₋₃alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and additionally R⁴ may preferably be selected from the    following three groups:-   8) C₂₋₃alkylX⁶C₂₋₃alkylR³³ (wherein X⁶ is as defined hereinbefore    and R³³ represents a 5 or 6 membered saturated heterocyclic group    with one or two heteroatoms, selected independently from O, S and N,    of which at least one is N, which heterocyclic group is linked to    C₂₋₃alkyl through a nitrogen atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, carbamoyl,    C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and    C₁₋₂alkoxycarbonyl);-   9) C₂₋₃alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two    substituents selected from oxo, C₁₋₂alkyl, C₁₋₂hydroxyalkyl,    carbamoyl, C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl    and C₁₋₂alkoxycarbonyl) with the proviso that when R⁴ is C₂    alkylR⁴³, X¹ is —S—, —SO—, —SO₂—, —SO₂NR⁹— or —NR¹⁰SO₂—); and-   10) C₂₋₃alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one    and optionally two substituents selected from oxo, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl).

An additional preferred value of R⁴ is C₂₋₃alkylX²methylX³R¹⁶ (whereinX² and X³ are as defined hereinbefore and R¹⁶ represents hydrogen orC₁₋₃alkyl) with the proviso that X¹ cannot be —CH₂— when R⁴ isC₂₋₃alkylX²methylX³R¹⁶.

More preferably R⁴ is selected from one of the following five groups:

-   1) C₁₋₃alkylR¹² (wherein R¹² is a group selected from    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl and    piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,    morpholin-3-yl and piperazin-2-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy, and additional possible    substituents are carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl) or    C₂₋₃alkylR⁴⁵ (wherein R⁴⁵ is a group selected from    imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy, and additional    possible substituents are carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl);-   2) 1-R⁵⁰but-2-en-4-yl (wherein R⁵ is a group selected from    imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl,    pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino and    thiomorpholino and piperidino which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy, and additional possible    substituents are carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl);-   3) 1-R⁵¹but-2-yn-4-yl (wherein R⁵¹ is a group selected from    imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl,    pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino and    thiomorpholino and piperidino which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy, and additional possible    substituents are carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl);-   4) C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶ (wherein X² and X³ are as defined    hereinbefore and R¹⁶ represents hydrogen or C₁₋₃alkyl) with the    proviso that X¹ cannot be —CH₂— when R⁴ is    C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶; and-   5) C₁₋₂alkoxyC₂₋₃alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and additionally R⁴ may more preferably be selected from the    following four groups:-   6) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl, 2-(1,3,3-trimethylureido)ethyl,    3-(1,3,3-trimethylureido)propyl, 2-(isopropoxycarbonylamino)ethyl,    3-(isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl,    3-(isobutoxycarbonylamino)propyl, 2-(t-butoxycarbonylamino)ethyl or    3-(t-butoxycarbonylamino)propyl;-   7) C₂₋₃alkylX⁵R²⁷ (wherein R²⁷ is C₁₋₂alkyl and X⁵ is —S—, —SO—,    —SO₂—, —SO₂NR³⁰— or —NR³¹SO₂— and with the proviso that X¹ is not    —CH₂—);-   8) C₂₋₃alkylR⁶C₂₋₃alkylR³³ (wherein X⁶ is as defined hereinbefore    and R³³ represents a group selected from morpholino,    2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl    and 4-methylpiperazin-1-yl); and-   9) C₂₋₃alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two    substituents selected from oxo, C₁₋₂alkyl, C₁₋₂hydroxyalkyl,    carbamoyl, C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl    and C₁₋₂alkoxycarbonyl) with the proviso that when R⁴ is    C₂₋₃alkylR⁴³, X¹ is —S—, —SO—, —SO₂—, —SO₂NR⁹— or —NR¹⁰SO₂—.

An additional more preferred value of R⁴ is C₂₋₃alkylX²methylX³R¹⁶(wherein X² and X³ are as defined hereinbefore and R¹⁶ representshydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be —CH₂— when R⁴is C₂₋₃alkylX²methylX³R¹⁶.

Most preferably R⁴ is selected from one of the following five groups:

-   1) C₁₋₃alkylR¹² (wherein R¹² is 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl or    pyrrolidin-3-yl or piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,    1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl,    1-methylpiperidin-4-yl, 1-methylpyrrolidin-2-yl,    1-methylpyrrolidin-3-yl, piperazin-2-yl, 1-methylpiperazin-2-yl,    4-methylpiperazin-2-yl, 1,4-dimethylpiperazin-2-yl, morpholin-2-yl,    morpholin-3-yl, 4-methylmorpholin-2-yl or 4-methylmorpholin-3-yl) or    C₂₋₃alkylR⁴⁵ (wherein R⁴⁵ is pyrrolidin-1-yl or thiomorpholino or    1,1-dioxothiomorpholino, 2-oxopyrrolidin-1-yl,    2-(N-methylcarbamoyl)pyrrolidin-1-yl,    2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl,    2-carbamoylpyrrolidin-1-yl, 2-oxoimidazolidin-1-yl or    3-methyl-2-oxoimidazolidin-1-yl);-   2) 1-R⁵⁰but-2-en-4-yl (wherein R⁵⁰ is 2-oxoimidazolidin-1-yl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, piperidin-4-yl, 1-methylpiperidin-4-yl,    pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino    or thiomorpholino or 4-methylpiperazin-1-yl, piperidino or    3-methyl-2-oxoimidazolidin-1-yl);-   3) 1-R⁵¹but-2-yn-4-yl (wherein R⁵¹ is 2-oxoimidazolidin-1-yl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, piperidin-4-yl, 1-methylpiperidin-4-yl,    pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino    or thiomorpholino or 4-methylpiperazin-1-yl, piperidino or    3-methyl-2-oxoimidazolidin-1-yl);-   4) C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶ (wherein X² and X³ are as defined    hereinbefore and R¹⁶ represents hydrogen or C₁₋₃alkyl) with the    proviso that X¹ cannot be —CH₂— when R⁴ is    C₂₋₃alkylX²C₂₋₃alkylX³R¹⁶; and-   5) C₁₋₂alkoxyC₂₋₃alkyl provided that X¹ is —S—, or X¹ is —SO— or    —SO₂—; and additionally R⁴ may most preferably be selected from the    following three groups:-   6) C₂₋₃alkylX⁵R²⁷ (wherein R²⁷ is C₁₋₂alkyl and X⁵ is —S—, —SO—,    —SO₂—, —SO₂NR³¹— or —NR³¹SO₂— and with the proviso that X¹ is not    —CH₂—);-   7) C₂₋₃alkylX⁶C₂₋₃alkylR³³ (wherein X⁶ is as defined hereinbefore    and R³³ represents a group selected from pyrrolidin-1-yl,    4-methylpiperazin-1-yl and morpholino); and-   8) C₂₋₃alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two    substituents selected from oxo, C₁₋₂alkyl, C₁₋₂hydroxyalkyl) with    the proviso that when R⁴ is C₂₋₃alkylR⁴³, X¹ is —S—, —SO—, —SO₂—,    —SO₂NR⁹— or —NR¹⁰SO₂—.

An additional most preferred value of R⁴ is C₂₋₃alkylX²methylX³R¹⁶(wherein X² and X³ are as defined hereinbefore and R¹⁶ representshydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be —CH₂— when R⁴is C₂₋₃alkylX²methylX³R¹⁶.

Especially preferred values for the group R⁴—X¹ are3-(methylsulphonyl)propoxy, (1-methylpiperidin-3-yl)methoxy,4-(pyrrolidin-1-yl)but-2-en-1-yloxy, 2-(2-methoxyethoxy)ethoxy,3-(1,1-dioxothiomorpholino)propoxy, 2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 3-morpholinopropylthio,2-([N-methoxyacetyl-N-methylamino)ethoxy,2-(2-oxopyrrolidin-1-yl)ethoxy, 2-thiomorpholinoethoxy,3-(2-carbamoylpyrrolidin-1-yl)propoxy, 3-(2-oxopyrrolidin-1-yl)propoxyand 2-(2-morpholinoethoxy)ethoxy.

More especially preferred values for the group R⁴—X¹ are3-(methylsulphonyl)propoxy, (1-methylpiperidin-3-yl)methoxy and4-(pyrrolidin-1-yl)but-2-en-1-yloxy.

In a particular aspect of the present invention there is provided acompound of the formula Ia:

[wherein:

-   R^(1a) is hydrogen or methoxy;-   R^(2a) is hydrogen;-   the phenyl group bearing (R^(3a))_(ma) is the    4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group;-   X^(1a) is —O—, —S—, —NR^(5a)CO— or —NR^(6a)SO₂— (wherein R^(5a) and    R^(6a) each independently represents hydrogen or C₁₋₂alkyl);-   R^(4a) is selected from one of the following eleven groups:-   1) C₁₋₄alkylR^(7a) (wherein R^(7a) is a group selected from    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,    1,3-dithian-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, and    piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,    morpholin-3-yl and piperazin-2-yl which group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl, C₁₋₃alkylcarbamoyl, N    N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl) or    C₂₋₄alkylR^(8a) (wherein R^(8a) is a group selected from    imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl);-   2) 1-R^(9a)prop-1-en-3-yl, 1-R^(9a)but-2-en-4-yl, 1-R⁹but-1-en-3-yl,    1-R^(9a)pent-2-en-4-yl or 2-R^(9a)pent-3-en-5-yl (wherein R^(9a) is    a 5 or 6 membered saturated heterocyclic group with one or two    heteroatoms, selected independently from O, S and N, which    heterocyclic group is linked to the alkenyl group through a carbon    atom and which heterocyclic group may bear one or two substituents    selected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃alkoxy, carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl) or    1-R^(10a)but-2-en-4-yl, 1-R^(10a)pent-2-en-4-yl or    2-R^(10a)pent-3-en-5-yl (wherein R^(10a) is a 5 or 6 membered    saturated heterocyclic group with one or two heteroatoms, of which    one is N and the other is selected independently from O, S and N,    which heterocyclic group is linked to the alkenyl group through a    nitrogen atom and which heterocyclic group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl, C₁₋₃alkylcarbamoyl,    N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and C₁₋₃alkoxycarbonyl);-   3) 1-R^(11a)prop-1-yn-3-yl, 1-R^(11a)but-2-yn-4-yl,    1-R^(11a)but-1-yn-3-yl, 1-R^(11a)pent-2-yn-4-yl or    2-R^(11a)pent-3-yn-5-yl (wherein R^(11a) is a 5 or 6 membered    saturated heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    the alkynyl group through a carbon atom and which heterocyclic group    may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl) or 1-R^(12a)but-2-yn-4-yl,    1-R^(12a)pent-2-yn-4-yl or 2-R^(12a)pent-3-yn-5-yl (wherein R^(12a)    is a 5 or 6 membered saturated heterocyclic group with one or two    heteroatoms, of which one is N and the other is selected    independently from O, S and N, which heterocyclic group is linked to    the alkynyl group through a nitrogen atom and which heterocyclic    group may bear one or two substituents selected from oxo, hydroxy,    halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl and    C₁₋₃alkoxycarbonyl);-   4) C₂₋₃alkylX^(2a)C₂₋₃alkylX^(3a)R^(13a) (wherein X^(2a) and X^(3a)    which may be the same or different each represents —O—, —S—, —SO—,    —SO₂—, —NR^(14a)CO_, or —NR^(15a)— (wherein R^(14a) and R^(15a) each    independently represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl) and    R¹³′ represents hydrogen or C₁₋₃alkyl);-   5) C₂₋₃alkylX^(4a)COR^(16a) (wherein X^(4a) represents —O— or    —NR^(17a)— (wherein R^(17a) represents hydrogen, C₁₋₃alkyl or    C₁₋₂alkoxyethyl) and R^(16a) represents —NR^(18a)R^(19a) or    —OR^(20a) (wherein R^(18a), R^(19a) and R^(20a) which may be the    same or different each represents hydrogen, C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   6) C₂₋₃alkylX^(5a)R^(21a) (wherein X^(5a) represents carbonyl, —O—,    —S—, —SO—, —SO₂—, —NR^(22a)CO—, —NR^(23a)SO₂— or NR^(24a)— (wherein    R^(22a), R^(23a) and R^(24a) each independently represents hydrogen,    C₁₋₂alkyl or C₁₋₂alkoxyethyl) and R^(21a) represents a group    selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl    which group is linked to X^(5a) through a carbon atom and which    group may carry one substituent selected from oxo, hydroxy,    halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, carbamoyl,    C₁₋₂alkylcarbamoyl, N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and    C₁₋₂alkoxycarbonyl or R^(21a) is C₁₋₃alkyl with the proviso that    when R^(21a) is C₁₋₃alkyl, X^(5a) is —S—, —SO—, —SO₂— or    —NR^(23a)SO₂—); and-   7) C₁₋₂alkoxyC₂₋₃alkyl provided that X^(6a) is —S—;-   8) C₂₋₃alkyX^(6a)C₂₋₃alkylR^(25a) (wherein X^(6a) represents —O—,    —S—, —SO—, —SO₂—, —NR^(26a)CO—, —NR^(27a)SO₂— or —NR^(28a)— (wherein    R^(26a), R^(27a) and R^(28a) each independently represents hydrogen,    C₁₋₂alkyl or C₁₋₂alkoxyethyl) and R^(25a) represents a 5 or 6    membered saturated heterocyclic group with one or two heteroatoms,    selected independently from O, S and N, which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, carbamoyl,    C₁₋₃alkylcarbamoyl, N,N-di(C₁₋₃alkyl)carbamoyl, C₂₋₃alkanoyl, and    C₁₋₃alkoxycarbonyl);-   9) C₂₋₃alkylR^(29a) (wherein R^(29a) is piperazin-1-yl which bears    at least one substituent selected from acetyl, C₁₋₂alkoxycarbonyl,    C₁₋₂hydroxyalkyl and CONR^(30a)R^(31a) (wherein R^(30a) and R^(31a)    each independently represents hydrogen or C₁₋₂alkyl);-   10) C₂₋₃alkylR^(32a) (wherein R^(32a) is morpholino which may bear    one or two substituents selected from oxo, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl) with the    proviso that when R^(4a) is C₂₋₃alkylR^(32a), X^(1a) is —S— or    —NR^(6a)SO₂— (wherein R^(6a) is as defined hereinbefore); and-   11) C₂₋₃alkylR^(33a) (wherein R^(33a) is morpholino which bears at    least one and optionally two substituents selected from oxo,    C₁₋₂alkyl, C₁₋₂hydroxyalkyl, carbamoyl, C₁₋₂alkylcarbamoyl,    N,N-di(C₁₋₂alkyl)carbamoyl, acetyl and C₁₋₂alkoxycarbonyl);    -   and an additional value of R^(4a) is        C₂₋₃alkylX^(2a)methylX^(3a)R^(13a) (wherein X^(2a) and X^(3a)        are as defined hereinbefore and R^(13a) represents hydrogen or        C₁₋₃alkyl);]        and salts thereof.

Preferred compounds of the present invention, by virtue of theirsubstantially equivalent activity against VEGF and EGF receptor tyrosinekinases include:

-   4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline.-   (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)quinazoline,-   7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline,-   4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxoimidazolidin-1-yl)ethoxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline    and-   4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline    and salts thereof especially hydrochloride salts thereof.

More preferred compounds of the present invention, by virtue of theirsubstantially equivalent activity against VEGF and EGF receptor tyrosinekinases include:

-   4-(4-chloro-2-fuoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline,-   (S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline,-   4-(4-chloro-2-fuoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline,-   (S)-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline    and-   4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline    and salts thereof especially hydrochloride salts thereof.

Particularly preferred compounds of the present invention, by virtue oftheir substantially equivalent activity against VEGF and EGF receptortyrosine kinases include:

-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-2-(2-methoxyethoxy)ethoxy)quinazoline    and-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline    and salts thereof especially hydrochloride salts thereof.

Additional particularly preferred compounds of the present invention, byvirtue of their substantially equivalent activity against VEGF and EGFreceptor tyrosine kinases include:

-   4-(4-bromo-2-fluoroanilino)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline,-   4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline,-   4′-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropylthio)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl]amino)ethoxy)quinazoline    and-   4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline    and salts thereof especially hydrochloride salts thereof.

Especially preferred compounds of the present invention, by virtue oftheir substantially equivalent activity against VEGF and EGF receptortyrosine kinases include:

-   (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline,-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline,-   (S)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline    and-   (R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline    and salts thereof especially hydrochloride salts thereof, of which    4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline    and salts thereof especially hydrochloride salts thereof, is more    especially preferred.

In a particular aspect of the present invention preferred compounds are:

-   4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline-   4-(4-chloro-2-fluoroanilino)-7-(2-(1,3-dioxolan-2-yl)ethoxy)-6-methoxyquinazoline-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline-   4-(4-chloro-2-fluoroanilino)-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-   4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline-   4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline    and salts thereof especially the hydrochloride salts thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsfor that group.

In this specification unless stated otherwise the term “alkyl” includesboth straight and branched chain alkyl groups but references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1-6 carbon atoms, preferably 1-4 carbon atoms. The term“alkoxy” as used herein, unless stated otherwise includes “alkyl”-O—groups in which “alkyl” is as hereinbefore defined. The term “aryl” asused herein unless stated otherwise includes reference to a C₆₋₁₀ arylgroup which may, if desired, carry one or more substituents selectedfrom halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (whereinalkyl and alkoxy are as hereinbefore defined). The term “aryloxy” asused herein unless otherwise stated includes “aryl”-O-groups in which“aryl” is as hereinbefore defined. The term “sulphonyloxy” as usedherein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which“alkyl” and “aryl” are as hereinbefore defined. The term “alkanoyl” asused herein unless otherwise stated includes formyl and alkylC═O groupsin which “alkyl” is as defined hereinbefore, for example C₂alkanoyl isethanoyl and refers to CH, C═O, C₁alkanoyl is formyl and refers to CHO.In this specification unless stated otherwise the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated the term “alkenyl”advantageously refers to chains with 2-5 carbon atoms, preferably 3-5carbon atoms. In this specification unless stated otherwise the term“alkynyl” includes both straight and branched chain alkynyl groups butreferences to individual alkynyl groups such as 2-butynyl are specificfor the straight chain version only. Unless otherwise stated the term“alkynyl” advantageously refers to chains with 2-5 carbon atoms,preferably 3-5 carbon atoms.

In formula I, as hereinbefore defined, hydrogen will be present atpositions 2 and 8 of the quinazoline group.

Within the present invention it is to be understood that a compound ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits VEGF receptor tyrosine kinase activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.

It is also to be understood that certain compounds of the formula I andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which inhibit VEGF receptor tyrosinekinase activity.

For the avoidance of any doubt, it is to be understood that when X¹ is,for example, a group of formula —NR⁷CO—, it is the nitrogen atom bearingthe R⁷ group which is attached to the quinazoline ring and the carbonyl(CO) group is attached to R⁴, whereas when X¹ is, for example, a groupof formula —CONR⁸—, it is the carbonyl group which is attached to thequinazoline ring and the nitrogen atom bearing the R⁸ group is attachedto R⁴. A similar convention applies to the other two atom X¹ linkinggroups such as —NR¹⁰SO₂— and —SO₂NR⁹—. When X¹ is —NR¹¹— it is thenitrogen atom bearing the R¹¹ group which is linked to the quinazolinering and to R⁴. An analogous convention applies to other groups, thuswhen R⁴ is, for example, a group of the formula C₁₋₅alkylX⁵R²⁷ and X⁵ isa group —NR²⁸CO—, it is the nitrogen atom bearing the R²² group which isattached to the alkyl chain which is attached to the quinazoline ringand the carbonyl (CO) group is attached to R²⁷, whereas when X⁵ is, forexample, a group of formula —CONR²⁹—, it is the carbonyl group which isattached to the alkyl chain which is attached to the quinazoline ringand the nitrogen atom bearing the R²⁹ group is attached to R²⁷. It isfurther to be understood that when X¹ represents —NR¹¹— and R¹¹ isC₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety which is linked to thenitrogen atom of X¹ and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁴ is, for example, a group of formulaC₁₋₅alkylX²C₁₋₅alkylX³R¹⁶, it is the terminal C₁₋₅alkyl moiety which isbound to X¹, similarly when R⁴ is, for example, a group of formulaC₂₋₅alkenylR¹⁴ it is the C₂₋₅alkenyl moiety which is bound to X¹ and ananalgous convention applies to other groups. When R⁴ is a group1-R³³prop-1-en-3-yl it is the first carbon to which the group R³³ isattached and it is the third carbon which is linked to X¹, similarlywhen R⁴ is a group 2-R³³pent-3-en-5-yl it is the second carbon to whichthe group R³³ is attached and it is the fifth carbon which is linked toX¹, and an analogous convention applies to other groups.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic or organic acidsaffording pharmaceutically acceptable anions such as with hydrogenhalides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid. Inaddition where the compounds of formula I are sufficiently acidic,pharmaceutically acceptable salts may be formed with an inorganic ororganic base which affords a pharmaceutically acceptable cation. Suchsalts with inorganic or organic bases include for example an alkalimetal salt, such as a sodium or potassium salt, an alkaline earth metalsalt such as a calcium or magnesium salt, an ammonium salt or forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A compound of the formula I, or salt thereof, and other compounds of theinvention (as hereinafter defined) may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes include, for example, those illustrated in EuropeanPatent Applications, Publication Nos. 0520722, 0566226, 0602851 and0635498. Such processes, are provided as a further feature of theinvention and are as described hereinafter. Necessary starting materialsmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.

Thus the following processes (a) to (g) and (i) to (v) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula III:

(wherein R¹, R², X¹ and R⁴ are as defined hereinbefore and L¹ is adisplaceable moiety), with a compound of the formula IV:

(wherein R³ and m are as defined hereinbefore) whereby to obtaincompounds of the formula I and salts thereof. A convenient displaceablemoiety L¹ is, for example, a halogeno, alkoxy (preferably C₁₋₄alkoxy),aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.

The reaction is advantageously effected in the presence of either anacid or a base. Such an acid is, for example, an anhydrous inorganicacid such as hydrogen chloride. Such a base is, for example, an organicamine base such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide. Alternatively such a base is, for example, analkali metal hydride, for example sodium hydride, or an alkali metal oralkaline earth metal amide, for example sodium amide or sodiumbis(trimethylsilyl)amide. The reaction is preferably effected in thepresence of an inert solvent or diluent, for example an alkanol or estersuch as methanol, ethanol, 2-propanol or ethyl acetate, a halogenatedsolvent such as methylene chloride, trichloromethane or carbontetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic hydrocarbon solvent such as toluene, or a dipolar aproticsolvent such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction isconveniently effected at a temperature in the range, for example, 10 to150° C., preferably in the range 20 to 80° C.

The compound of the invention may be obtained from this process in theform of the free base or alternatively it may be obtained in the form ofa salt with the acid of the formula H-L¹ wherein L¹ has the meaningdefined hereinbefore. When it is desired to obtain the free base fromthe salt, the salt may be treated with a base as defined hereinbeforeusing a conventional procedure.

(b) Where the group of formula IIa:

(wherein R³ and m are as hereinbefore defined) represents a phenyl groupcarrying one or more hydroxy groups, a compound of the formula I andsalts thereof can be prepared by the deprotection of a compound offormula V:

(wherein X¹, m, R¹, R², R³ and R⁴ are as hereinbefore defined, Prepresents a phenolic hydroxy protecting group and p1 is an integer from1 to 5 equal to the number of protected hydroxy groups and such thatm-p1 is equal to the number of R³ substituents which are not protectedhydroxy). The choice of phenolic hydroxy protecting group P is withinthe standard knowledge of an organic chemist, for example those includedin standard texts such as “Protective Groups in Organic Synthesis” T. W.Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, including ethers (forexample, methyl, methoxymethyl, allyl and benzyl and benzyl substitutedwith up to two substituents selected from C₁₋₄alkoxy and nitro), silylethers (for example, t-butyldiphenylsilyl and t-butyldimethylsilyl),esters (for example, acetate and benzoate) and carbonates (for example,methyl and benzyl and benzyl substituted with up to two substituentsselected from C₁₋₄alkoxy and nitro). The removal of such a phenolichydroxy protecting group may be effected by any of the procedures knownfor such a transformation, including those reaction conditions indicatedin standard texts such as that indicated hereinbefore, or by a relatedprocedure. The reaction conditions preferably being such that thehydroxy derivative is produced without unwanted reactions at other siteswithin the starting or product compounds. For example, where theprotecting group P is acetate, the transformation may conveniently beeffected by treatment of the quinazoline derivative with a base asdefined hereinbefore and including ammonia, and its mono anddi-alkylated derivatives, preferably in the presence of a protic solventor co-solvent such as water or an alcohol, for example methanol orethanol. Such a reaction can be effected in the presence of anadditional inert solvent or diluent as defined hereinbefore and at atemperature in the range 0 to 50° C., conveniently at about 20° C.

(c) Production of those compounds of formula I and salts thereof whereinthe substituent X¹ is —O—, —S— or —NR¹¹— or —SO₂—, —CONR⁸— or —SO₂NR⁹—can be achieved by the reaction, conveniently in the presence of a baseas defined hereinbefore, of a compound of the formula VI:

(wherein m, X¹, R¹, R² and R³ are as hereinbefore defined) with acompound of formula VII:R⁴L¹  (VII)(wherein R⁴ and L¹ are as hereinbefore defined); L¹ is a displaceablemoiety for example a halogeno or sulphonyloxy group such as a bromo ormethanesulphonyloxy group. Conveniently L¹ is a group O—⁺P(R⁵²)₃(wherein R⁵² is butyl or phenyl) and in such cases the compound offormula VII is conveniently formed in situ. The reaction is preferablyeffected in the presence of a base (as defined hereinbefore in process(a)) and advantageously in the presence of an inert solvent or diluent(as defined hereinbefore in process (a)), advantageously at atemperature in the range, for example 10 to 150° C., conveniently atabout 50° C.

(d) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula VIII:

with a compound of the formula IX:R⁴—X¹′H  (IX)(wherein L¹, R¹, R², R³, R⁴, m and X¹ are all as hereinbefore defined).The reaction may conveniently be effected in the presence of a base (asdefined hereinbefore in process (a)) and advantageously in the presenceof an inert solvent or diluent (as defined hereinbefore in process (a)),advantageously at a temperature in the range, for example 10 to 150° C.,conveniently at about 100° C.

(e) Compounds of the formula I and salts thereof wherein R⁴ isC₁₋₅alkylR⁵³, [wherein R⁵³ is selected from one of the following threegroups:

-   1) X⁷R²⁷ (wherein X⁷ represents —O—, —S—, —SO₂—, —NR⁵⁴CO—, —NR⁵⁵SO₂—    or —NR⁵⁶— (wherein R⁵⁴, R⁵⁵ and R⁵⁶ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is as defined    hereinbefore); and-   2) X⁸C₁₋₅alkylX³R¹⁶ (wherein X⁸ represents —O—, —S—, —SO—, —NR⁵⁷CO—,    —NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁷, R⁵⁸ and R⁵⁹ each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and X³ and    R¹⁶ are as defined hereinbefore); and-   3) X⁹C₁₋₅alkylR³³ (wherein X⁹ represents —O—, —S—, —SO₂—, —NR⁶⁰CO—,    —NR⁶¹SO₂— or —NR⁶²— (wherein R⁶⁰, R⁶¹ and R⁶² each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as    defined hereinbefore);]    may be prepared by reacting a compound of the formula X:    (wherein L¹, X¹, R¹, R², R³ and m are as hereinbefore defined and    R⁶³ is C₁₋₅alkyl) with a compound of the formula XI:    R⁵³—H  (XI)    (wherein R⁵³ is as defined hereinbefore) to give a compound of the    formula I. The reaction may conveniently be effected in the presence    of a base (as defined hereinbefore in process (a)) and    advantageously in the presence of an inert solvent or diluent (as    defined hereinbefore in process (a)), and at a temperature in the    range, for example 0 to 150° C., conveniently at about 50° C.

Compounds of the formula I wherein R⁴ is C₂₋₅alkylR⁴⁵, (wherein R⁴⁵ isas defined hereinbefore), may be prepared by reacting a compound offormula X (wherein R⁶³ is C₂₋₅alkyl) with a compound of the formula XIa:R⁴⁵—H  (XIa)(wherein R⁴⁵ is as defined hereinbefore) to give a compound of theformula I. The reaction may conveniently be effected in the presence ofa base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), and at a temperature in the range, for example 0 to 150°C., conveniently at about 50° C.

(f) The production of those compounds of the formula I and salts thereofwherein the substituent R¹ is represented by —NR⁵R⁶, where one or bothof R⁵ and R⁶ are C₁₋₃alkyl, may be effected by the reaction of compoundsof formula I wherein the substituent R¹ is an amino group and analkylating agent, preferably in the presence of a base as definedhereinbefore. Such alkylating agents are C₁₋₃alkyl moieties bearing adisplaceable moiety as defined hereinbefore such as C₁₋₃alkyl halidesfor example C₁₋₃alkyl chloride, bromide or iodide. The reaction ispreferably effected in the presence of an inert solvent or diluent (asdefined hereinbefore in process (a)) and at a temperature in the range,for example, 10 to 100° C. conveniently at about ambient temperature.

(g) The production of compounds of formula I and salts thereof whereinone or more of the substituents R¹, R² or R³ is an amino group may beeffected by the reduction of a corresponding compound of formula Iwherein the substituent(s) at the corresponding position(s) of thequinazoline and/or aniline ring is/are a nitro group(s). The reductionmay conveniently be effected as described in process (i) hereinafter.The production of a compound of formula I and salts thereof wherein thesubstituent(s) at the corresponding position(s) of the quinazolineand/or aniline ring is/are a nitro group(s) may be effected by theprocesses described hereinbefore and hereinafter in processes (a-e) and(i-v) using a quinazoline compound selected from the compounds of theformulae (I-XXVII) in which the substituent(s) at the correspondingposition(s) of the quinazoline and/or aniline ring is/are a nitrogroup(s).

Synthesis of Intermediates

(i) The compounds of formula III and salts thereof, constitute a furtherfeature of the present invention. Such compounds in which L¹ is halogenomay for example be prepared by halogenating a compound of the formulaXII:

(wherein R¹, R², R⁴ and X¹ are as hereinbefore defined).

Convenient halogenating agents include inorganic acid halides, forexample thionyl chloride, phosphorus(III)chloride,phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenationreaction is conveniently effected in the presence of an inert solvent ordiluent such as for example a halogenated solvent such as methylenechloride, trichloromethane or carbon tetrachloride, or an aromatichydrocarbon solvent such as benzene or toluene. The reaction isconveniently effected at a temperature in the range, for example 10 to150° C., preferably in the range 40 to 100° C.

The compounds of formula XII and salts thereof which constitute afurther feature of the present invention may for example be prepared byreacting a compound of the formula XIII:

(wherein R¹, R² and L¹ are as hereinbefore defined) with a compound ofthe formula IX as hereinbefore defined. The reaction may conveniently beeffected in the presence of a base (as defined hereinbefore in process(a)) and advantageously in the presence of an inert solvent or diluent(as defined hereinbefore in process (a)), advantageously at atemperature in the range for example 10 to 150° C., conveniently atabout 100° C.

The compounds of formula XII and salts thereof may also be prepared bycyclising a compound of the formula XIV:

(wherein R¹, R², R⁴ and X¹, are as hereinbefore defined, and A¹ is anhydroxy, alkoxy (preferably C₁₋₄alkoxy) or amino group) whereby to forma compound of formula XII or salt thereof. The cyclisation may beeffected by reacting a compound of the formula XIV, where A¹ is anhydroxy or alkoxy group, with formamide or an equivalent thereofeffective to cause cyclisation whereby a compound of formula XII or saltthereof is obtained, such as[3-(dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride. Thecyclisation is conveniently effected in the presence of formamide assolvent or in the presence of an inert solvent or diluent such as anether for example 1,4-dioxan. The cyclisation is conveniently effectedat an elevated temperature, preferably in the range 80 to 200° C. Thecompounds of formula XII may also be prepared by cyclising a compound ofthe formula XIV, where A¹ is an amino group, with formic acid or anequivalent thereof effective to cause cyclisation whereby a compound offormula XII or salt thereof is obtained. Equivalents of formic acideffective to cause cyclisation include for example atri-C₁₋₄alkoxymethane, for example triethoxymethane andtrimethoxymethane. The cyclisation is conveniently effected in thepresence of a catalytic amount of an anhydrous acid, such as a sulphonicacid for example p-toluenesulphonic acid, and in the presence of aninert solvent or diluent such as for example a halogenated solvent suchas methylene chloride, trichloromethane or carbon tetrachloride, anether such as diethylether or tetrahydrofuran, or an aromatichydrocarbon solvent such as toluene. The cyclisation is convenientlyeffected at a temperature in the range, for example 10 to 100° C.preferably in the range 20 to 50° C.

Compounds of formula XIV and salts thereof, which constitute a furtherfeature of the present invention, may for example be prepared by thereduction of the nitro group in a compound of the formula XV:

(wherein R¹, R², R⁴, X¹ and A¹ are as hereinbefore defined) to yield acompound of formula XIV as hereinbefore defined. The reduction of thenitro group may conveniently be effected by any of the procedures knownfor such a transformation. The reduction may be carried out, forexample, by the hydrogenation of a solution of the nitro compound in thepresence of an inert solvent or diluent as defined hereinbefore in thepresence of a metal effective to catalyse hydrogenation reactions suchas palladium or platinum. A further reducing agent is, for example, anactivated metal such as activated iron (produced for example by washingiron powder with a dilute solution of an acid such as hydrochloricacid). Thus, for example, the reduction may be effected by heating thenitro compound and the activated metal in the presence of a solvent ordiluent such as a mixture of water and alcohol, for example methanol orethanol, to a temperature in the range, for example 50 to 150° C.,conveniently at about 70° C.

Compounds of the formula XV and salts thereof which constitute a furtherfeature of the present invention, may for example be prepared by thereaction of a compound of the formula XVI:

(wherein R¹, R², L¹ and A¹ are as hereinbefore defined) with a compoundof the formula IX as hereinbefore defined to give a compound of theformual XV. The reaction of the compounds of formulae XVI and IX isconveniently effected under conditions as described for process (d)hereinbefore.

Compounds of formula XV and salts thereof, may for example also beprepared by the reaction of a compound of the formula XVII:

(wherein R¹, R², X¹ and A¹ are as hereinbefore defined with the provisothat X¹ is not —CH₂—) with a compound of the formula VII as hereinbeforedefined to yield a compound of formula XV as hereinbefore defined. Thereaction of the compounds of formulae XVII and VII is convenientlyeffected under conditions as described for process (c) hereinbefore.

The compounds of formula III and salts thereof may also be prepared forexample by reacting a compound of the formula XVIII:

(wherein R¹, R² and X¹ are as hereinbefore defined with the proviso thatX¹ is not —CH₂— and L² represents a displaceable protecting moiety) witha compound of the formula VII as hereinbefore defined, whereby to obtaina compound of formula III in which L¹ is represented by L².

A compound of formula XVIII is conveniently used in which L² representsa phenoxy group which may if desired carry up to 5 substituents,preferably up to 2 substituents, selected from halogeno, nitro andcyano. The reaction may be conveniently effected under conditions asdescribed for process (c) hereinbefore.

The compounds of formula XVIII and salts thereof as hereinbefore definedmay for example be prepared by deprotecting a compound of the formulaXIX:

(wherein R¹, R², P, X¹ and L² are as hereinbefore defined with theproviso that X¹ is not —CH₂—). Deprotection may be effected bytechniques well known in the literature, for example where P representsa benzyl group deprotection may be effected by hydrogenolysis or bytreatment with trifluoroacetic acid.

One compound of formula III may if desired be converted into anothercompound of formula III in which the moiety L¹ is different. Thus forexample a compound of formula III in which L¹ is other than halogeno,for example optionally substituted phenoxy, may be converted to acompound of formula III in which L¹ is halogeno by hydrolysis of acompound of formula III (in which L¹ is other than halogeno) to yield acompound of formula XII as hereinbefore defined, followed byintroduction of halide to the compound of formula XII, thus obtained ashereinbefore defined, to yield a compound of formula III in which L¹represents halogen.

(ii) The compounds of formula V and salts thereof, constitute a furtherfeature of the present invention, and may for example be prepared by thereaction of a compound of formula III as hereinbefore defined with acompound of the formula XX:

(wherein R′, m, p1 and P are as hereinbefore defined). The reaction mayfor example be effected as described for process (a) hereinbefore.

The compounds of formula V and salts thereof may also be prepared byreacting a compound of formula XXI:

(wherein R¹, R², L¹, R³, m, p1 and P are as hereinbefore defined) with acompound of formula IX as hereinbefore defined. The reaction may forexample be effected as described for process (d) above.

The compounds of formula V and salts thereof may also be prepared byreacting a compound of formula XXII:

(wherein R¹, R², R³, X¹, P, p1 and m are as hereinbefore defined withthe proviso that X¹ is not —CH₂—) with a compound of the formula VII ashereinbefore defined. The reaction may for example be effected asdescribed for process (c) hereinbefore.

The compounds of formula XXI and salts thereof may for example beprepared by reaction of a compound of formula XXIII:

(wherein R¹, R², and L¹ are as hereinbefore defined, and L¹ in the 4-and 7-positions may be the same or different) with a compound of theformula XX as hereinbefore defined. The reaction may be effected forexample by a process as described in (a) above.

Compounds of the formula XXII and salts thereof may be made by reactingcompounds of the formulae XIX and XX as hereinbefore defined, underconditions described in (a) hereinbefore, to give a compound of formulaXXIV:

(wherein R¹, R², R³, P, X¹, p1 and m are as hereinbefore defined withthe proviso that X¹ is not —CH₂—) and then deprotecting the compound offormula XXIV for example as described in (i) above.

(iii) Compounds of the formula VI as hereinbefore defined and saltsthereof may be made by deprotecting the compound of formula XXV:

(wherein R¹, R², R³, P, X¹ and m are as hereinbefore defined) by aprocess for example as described in (i) above.

Compounds of the formula XXV and salts thereof may be made by reactingcompounds of the formulae XIX and IV as hereinbefore defined, under theconditions described in (a) hereinbefore, to give a compound of theformula XXV or salt thereof.

(iv) Compounds of the formula VIII and salts thereof as hereinbeforedefined may be made by reacting compounds of the formulae XXIII and IVas hereinbefore defined, the reaction for example being effected by aprocess as described in (a) above.

(v) Compounds of the formula X as defined hereinbefore and salts thereofmay for example be made by the reaction of a compound of formula VI asdefined hereinbefore with a compound of the formula XXVI:L¹-R⁶³-L¹  (XXVI)(wherein L¹ and R⁶³ are as hereinbefore defined) to give a compound ofthe formula X. The reaction may be effected for example by a process asdescribed in (c) above.

Compounds of the formula X and salts thereof may also be made forexample by deprotecting a compound of the formula XXVII:

(wherein L¹, R⁶³, X¹, R¹, R², R³, P, m and p1 are as definedhereinbefore) by a process for example as described in (b) above.

Compounds of the formula XXVII and salts thereof may be made for exampleby reacting compounds of the formulae XXII and XXVI as definedhereinbefore, under the conditions described in (c) above.

When a pharmaceutically acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with, for example, an acid using a conventional procedure, theacid having a pharmaceutically acceptable anion.

Many of the intermediates defined herein are novel, for example, thoseof the formulae III, V, XII, XIV and XV, and these are provided as afurther feature of the invention.

Intermediates of the formulae VIII, X, XXI, XXII, XXIV, XXV and XXVIIare also provided as a further feature of the invention.

The identification of compounds which potently inhibit the tyrosinekinase activity associated with the VEGF receptors such as Fit and/orKDR and which inhibit angiogenesis and/or increased vascularpermeability is desirable and is the subject of the present invention.These properties may be assessed, for example, using one or more of theprocedures set out below:

(a) In Vitro Receptor Tyrosine Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit tyrosinekinase activity. DNA encoding VEGF or epidermal growth factor (EGF)receptor cytoplasmic domains may be obtained by total gene synthesis(Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or bycloning. These may then be expressed in a suitable expression system toobtain polypeptide with tyrosine kinase activity. For example VEGF andEGF receptor cytoplasmic domains, which were obtained by expression ofrecombinant protein in insect cells, were found to display intrinsictyrosine kinase activity. In the case of the VEGF receptor Flt (Genbankaccession number X51602), a 1.7 kb DNA fragment encoding most of thecytoplasmic domain, commencing with methionine 783 and including thetermination codon, described by Shibuya et al (Oncogene, 1990, 5:519-524), was isolated from cDNA and cloned into a baculovirustransplacement vector (for example pAcYM1 (see The BaculovirusExpression System: A Laboratory Guide, L. A. King and R. D. Possee,Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available fromInvitrogen Corporation)). This recombinant construct was co-transfectedinto insect cells (for example Spodoptera frugiperda 21(Sf21)) withviral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.(Details of the methods for the assembly of recombinant DNA moleculesand the preparation and use of recombinant baculovirus can be found instandard texts for example Sambrook et al, 1989, Molecular cloning—ALaboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press andO'Reilly et al, 1992, Baculovirus Expression Vectors—A LaboratoryManual, W. H. Freeman and Co, New York). For other tyrosine kinases foruse in assays, cytoplasmic fragments starting from methionine 806 (KDR,Genbank accession number L04947) and methionine 668 (EGF receptor,Genbank accession number X00588) may be cloned and expressed in asimilar manner.

For expression of cFlt tyrosine kinase activity, Sf21 cells wereinfected with plaque-pure cFlt recombinant virus at a multiplicity ofinfection of 3 and harvested 48 hours later. Harvested cells were washedwith ice cold phosphate buffered saline solution (PBS) (10 mM sodiumphosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) thenresuspended in ice cold HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodiumchloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5 mM magnesiumchloride, 1 mM ethylene glycol-bis(βaminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonylfluoride); the PMSF is added just before use from a freshly-prepared 100mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. Thesuspension was centrifuged for 10 minutes at 13,000 rpm at 4° C., thesupernatant (enzyme stock) was removed and stored in aliquots at −70° C.Each new batch of stock enzyme was titrated in the assay by dilutionwith enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM sodium orthovanadate,0.1% v/v Triton X100, 0.2 mM dithiothreitol). For a typical batch, stockenzyme is diluted 1 in 2000 with enzyme diluent and 50 μl of diluteenzyme is used for each assay well.

A stock of substrate solution was prepared from a random copolymercontaining tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (SigmaP3899), stored as 1 mg/ml stock in PBS at −20° C. and diluted 1 in 500with PBS for plate coating.

On the day before the assay 100 μl of diluted substrate solution wasdispensed into all wells of assay plates (Nunc maxisorp 96-wellimmunoplates) which were sealed and left overnight at 4° C.

On the day of the assay the substrate solution was discarded and theassay plate wells were washed once with PBST (PBS containing 0.05% v/vTween 20) and once with 50 mM Hepes pH7.4.

Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μlof diluted compound was transferred to wells in the washed assay plates.“Total” control wells contained 10% DMSO instead of compound. Twentylive microlitres of 40 mM manganese(II)chloride containing 8 μMadenosine-5′-triphosphate (ATP) was added to all test wells except“blank” control wells which contained manganese(II)chloride without ATP.To start the reactions 50 μl of freshly diluted enzyme was added to eachwell and the plates were incubated at room temperature for 20 minutes.The liquid was then discarded and the wells were washed twice with PBST.One hundred microlitres of mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05-321), diluted 1 in 6000 with PBSTcontaining 0.5% w/v bovine serum albumin (BSA), was added to each welland the plates were incubated for 1 hour at room temperature beforediscarding the liquid and washing the wells twice with PBST. One hundredmicrolitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Igantibody (Amersham product NXA 931), diluted 1 in 500 with PBSTcontaining 0.5% w/v BSA, was added and the plates were incubated for 1hour at room temperature before discarding the liquid and washing thewells twice with PBST. One hundred microlitres of2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution,freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodiumperborate (made with 1 phosphate citrate buffer with sodium perborate(PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added toeach well. Plates were then incubated for 20-60 minutes at roomtemperature until the optical density value of the “total” controlwells, measured at 405 nm using a plate reading spectrophotometer, wasapproximately 1.0. “Blank” (no ATP) and “total” (no compound) controlvalues were used to determine the dilution range of test compound whichgave 50% inhibtion of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (HUVEC).

HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v foetal calfserum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/vFCS+3 μg/ml heparin+1 μg/ml hydrocortisone, at a concentration of 1000cells/well in 96 well plates. After a minimum of 4 hours they were dosedwith the appropriate growth factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml orb-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4days at 37° C. with 7.5% carbon dioxide. On day 4 the cultures werepulsed with 1 μCi/well of tritiated-thymidine (Amersham product TRA 61)and incubated for 4 hours. The cells were harvested using a 96-wellplate harvester (Tomtek) and then assayed for incorporation of tritiumwith a Beta plate counter. Incorporation of radioactivity into cells,expressed as cpm, was used to measure inhibition of growthfactor-stimulated cell proliferation by compounds.

(c) In Vivo Rat Uterine Oedema Assay

This test measures the capacity of compounds to reduce the acuteincrease in uterine weight in rats which occurs in the first 4-6 hoursfollowing oestrogen stimulation. This early increase in uterine weighthas long been known to be due to oedema caused by increased permeabilityof the uterine vasculature and recently Cullinan-Bove and Koos(Endocrinology, 1993, 133:829-837) demonstrated a close temporalrelationship with increased expression of VEGF mRNA in the uterus. Wehave found that prior treatment of the rats with a neutralisingmonoclonal antibody to VEGF significantly reduces the acute increase inuterine weight, confirming that the increase in weight is substantiallymediated by VEGF.

Groups of 20 to 22-day old rats were treated with a single subcutaneousdose of oestradiol benzoate (2.5 μg/rat) in a solvent, or solvent only.The latter served as unstimulated controls. Test compounds were orallyadministered at various times prior to the administration of oestradiolbenzoate. Five hours after the administration of oestradiol benzoate therats were humanely sacrificed and their uteri were dissected, blottedand weighed. The increase in uterine weight in groups treated with testcompound and oestradiol benzoate and with oestradiol benzoate alone wascompared using a Student T test. Inhibition of the effect of oestradiolbenzoate was considered significant when p<0.05.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula Ias defined hereinbefore or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) forexample as a sterile solution, suspension or emulsion, for topicaladministration for example as an ointment or cream or for rectaladministration for example as a suppository. In general the abovecompositions may be prepared in a conventional manner using conventionalexcipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremetre body area of the animal, i.e. approximately 0.1-100 mg/kg. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1-250 mg of active ingredient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

We have found that compounds of the present invention inhibit VEGFreceptor tyrosine kinase activity and are therefore of interest fortheir antiangiogenic effects and/or their ability to cause a reductionin vascular permeability.

A further feature of the present invention is a compound of formula I,or a pharmaceutically acceptable salt thereof, for use as a medicament,conveniently a compound of formula I, or a pharmaceutically acceptablesalt thereof, for use as a medicament for producing an antiangiogenicand/or vascular permeability reducing effect in a warm-blooded animalsuch as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of an antiangiogenic and/or vascular permeability reducingeffect in a warm-blooded animal such as a human being.

According to a further feature of the invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal, such as a human being, in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The antiangiogenic and/or vascular permeability reducing treatmentdefined hereinbefore may be applied as a sole therapy or may involve, inaddition to a compound of the invention, one or more other substancesand/or treatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. In the field of medical oncology it isnormal practice to use a combination of different forms of treatment totreat each patient with cancer. In medical oncology the othercomponent(s) of such conjoint treatment in addition to theantiangiogenic and/or vascular permeability reducing treatment definedhereinbefore may be: surgery, radiotherapy or chemotherapy. Suchchemotherapy may cover three main categories of therapeutic agent:

-   (i) other antiangiogenic agents that work by different mechanisms    from those defined hereinbefore (for example linomide, inhibitors of    integrin αvβ3 function, angiostatin, razoxin, thalidomide);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LHRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors); and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites (for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincristine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan).

As stated above the compounds defined in the present invention are ofinterest for their antiangiogenic and/or vascular permeability reducingeffects. Such compounds of the invention are expected to be useful in awide range of disease states including cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation. Inparticular such compounds of the invention are expected to slowadvantageously the growth of primary and recurrent solid tumours of, forexample, the colon, breast, prostate, lungs and skin. More particularlysuch compounds of the invention are expected to inhibit the growth ofthose primary and recurrent solid tumours which are associated with VEGFespecially those tumours which are significantly dependent on VEGF fortheir growth and spread, including for example, certain tumours of thecolon, breast, prostate, lung, vulva and skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof VEGF receptor tyrosine kinase activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:—

-   -   [(i) evaporations were carried out by rotary evaporation in        vacuo and work-up procedures were carried out after removal of        residual solids such as drying agents by filtration;    -   (ii) operations were carried out at ambient temperature, that is        in the range 18-25° C. and under an atmosphere of an inert gas        such as argon;    -   (iii) column chromatography (by the flash procedure) and medium        pressure liquid chromatography (MPLC) were performed on Merck        Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18        (Art. 9303) reversed-phase silica obtained from E. Merck,        Darmstadt, Germany;    -   (iv) yields are given for illustration only and are not        necessarily the maximum attainable;    -   (v) melting points are uncorrected and were determined using a        Mettler SP62 automatic melting point apparatus, an oil-bath        apparatus or a Koffler hot plate apparatus.    -   (vi) the structures of the end-products of the formula I were        confirmed by nuclear (generally proton) magnetic resonance (NMR)        and mass spectral techniques; proton magnetic resonance chemical        shift values were measured on the delta scale and peak        multiplicities are shown as follows: s, singlet; d, doublet; t,        triplet; m, multiplet; br, broad; q, quartet;    -   (vii) intermediates were not generally fully characterised and        purity was assessed by thin layer chromatography (TLC),        high-performance liquid chromatography (HPLC), infra-red (IR) or        NMR analysis;    -   (viii) the following abbreviations have been used:—        -   DMF N,N-dimethylformamide        -   DMSO dimethylsulphoxide        -   THF tetrahydrofuran        -   TFA trifluoroacetic acid        -   NMP 1-methyl-2-pyrrolidinone.]

EXAMPLE 1

Potassium carbonate (2.2 g, 16 mmol) was added to a solution of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.51 g, 4mmol) in DMF (30 ml) and the mixture stirred for 15 minutes.2-Bromoethyl methyl ether (667 mg, 4.8 mmol) was then added dropwise.The mixture was stirred for 1 hour at ambient temperature, then heatedat 60° C. for 17 hours and finally allowed to cool. The insolublematerial was removed by filtration and the filter pad washed with DMF.The filtrate was partitioned between ethyl acetate and water, theorganic layer was separated, washed with brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (95/5 followedby 93/7). The purified product was triturated with ether to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline(1.34 g, 84%) as a white powder.

m.p. 180-183° C.

¹H NMR Spectrum: (CDCl₃) 2.16 (s, 3H); 2.34 (s 3H); 3.47 (s, 3H); 3.87(t, 2H); 3.99 (s, 3H); 4.31 (t, 2H); 6.98 (s, 1H); 7.21 (d, 1H); 7.24(d, 1H); 7.42 (d, 1H); 7.50 (s, 1H); 8.64 (s, 1H)

MS-ESI: 420 [MNa]⁺ Elemental analysis: Found C 63.1 H 6.1 N 10.4C₂₁H₂₃N₃O₅ Requires C 63.5 H 5.8 N 10.6%

The starting material was prepared as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem. 1977,vol 20, 146-149, 10 g, 0.04 mol) and Gold's reagent (7.4 g, 0.05 mol) indioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodiumacetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) wereadded to the reaction mixture and it was heated for a further 3 hours.The mixture was evaporated, water was added to the residue, the solidwas filtered off, washed with water and dried (MgSO₄). Recrystallisationfrom acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one(8.7 g, 84%).

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g,0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred andheated to reflux for 1 hour. The mixture was evaporated, the residue wastaken up in toluene and evaporated to dryness to give7-benzyloxy-4-chloro-6-methoxyquinazoline (3.45 g).

Acetic anhydride (1.9 ml, 20.3 mmol) was added to a mixture of2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueous sodiumhydroxide (24.5 ml) at ambient temperature. The mixture was stirred for40 minutes, the solid was removed by filtration and the filtrateextracted with ethyl acetate. The organic layers were combined, washedwith an aqueous saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture ofthis material (3.1 g, 15.9 mmol) and 10% palladium-on-charcoal catalyst(0.12 g) in ethyl acetate (50 ml) was stirred at ambient temperatureunder an atmosphere of hydrogen for 2 hours. The catalyst was removed byfiltration and the filtrate evaporated to give 3-acetoxy-4-methylaniline(2.45 g, 94%).

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (2.18 g, 7.25mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml)was stirred and heated to reflux for 1 hour. The mixture was cooled toambient temperature. The precipitate was collected by filtration, washedwith 2-propanol and ether to give4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline. Amixture of4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g,5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambienttemperature under 1.5 atmospheres of hydrogen for 30 minutes. Thecatalyst was removed by filtration and the filtrate evaporated. Theresidual solid was triturated in ether, collected by filtration anddried under vacuum at 50° C. to give4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g,100%).

EXAMPLE 2

A solution of 2-(2-bromoethyl)-1,3-dioxolane (258 mg, 1.4 mmol) in DMF(0.5 ml) was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (329 mg,1.02 mmol) and potassium carbonate (264 mg, 2 mmol) in DMF (2 ml). Themixture was heated at 100° C. for 3 hours and allowed to cool. Thevolatiles were removed by evaporation, and the residue partitionedbetween aqueous sodium hydrogen carbonate solution and methylenechloride. The organic phase was separated and passed through phaseseparating paper. The solvent was removed by evaporation, and theresidue was purified by column chromatography eluting with methylenechloride/methanol (95/5) to give4-(4-chloro-2-fluoroanilino)-7-(2-(1,3-dioxolan-2-yl)ethoxy)-methoxyquinazoline(71 mg, 17%).

¹H NMR Spectrum: (DMSOd₆) 2.1 (m, 2H,); 3.8 (m, 2H); 3.95 (m, 5H); 4.25(t, 2H); 5.05 (t, 1H); 7.18 (s, 1H); 7.3 (m, 1H); 7.55 (m, 2H); 7.8 (s,1H); 8.35 (s, 1H); 9.5 (s, 1H)

MS-ESI: 420 [MH]⁺ Elemental analysis: Found C 57.4 H 4.7 N 9.1C₂₀H₁₉N₃O₄ClF Requires C 57.2 H 5.6 N 10.0%

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.2 g, 4 mmol),(prepared as described for the starting material in Example 1), and4-chloro-2-fluoroaniline (444 μl, 4 mmol) in 2-propanol (40 ml) wasrefluxed for 1.5 hours. After cooling, the precipitate was collected byfiltration, washed with 2-propanol then ether and dried under vacuum togive 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (1.13 g, 64%).

m.p. 239-242° C.

¹H NMR Spectrum: (DMSOd₆) 4.0 (s, 3H); 5.36 (s, 2H); 7.39-7.52 (m, 9H);8.1 (s, 1H); 8.75 (s,

-   1H)

MS-ESI: 410 [MH]⁺ Elemental analysis: Found C 59.2 H 4.3 N 9.4C₂₂H₁₇N₃O₂ClF 1HCl Requires C 59.2 H 4.1 N 9.41%

A solution of7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (892 mg, 2 mmol) in TFA (10 ml) was refluxed for 50minutes. After cooling, the mixture was poured onto ice. The precipitatewas collected by filtration, dissolved in methanol (10 ml) and basifiedto pH11 with aqueous ammonia. After concentration by evaporation, thesolid product was collected by filtration, washed with water then etherand dried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline as a yellowsolid (460 mg, 72%).

m.p. 141-143° C.

¹H NMR Spectrum: (DMSOd₆) 3.95 (s, 3H); 7.05 (s, 1H); 7.35 (d, 1H);7.54-7.59 (m, 2H); 7.78 (s, 1H); 8.29 (s, 1H)

MS-ESI: 320-322 [MH]⁺

EXAMPLE 3

1-(2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was addedto a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg,1.26 mmol), (prepared as described for the starting material in Example2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). Themixture was heated to 100° C. and further portions of1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were addedperiodically over 4 hours while the reaction mixture was maintained at100° C. The reaction was then allowed to cool and volatiles were removedby evaporation. The residue was partitioned between methylene chlorideand water, separated and the organic phase passed through phaseseparating paper. Column chromatography eluting with methylenechloride/methanol (95/5) gave4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline(50 mg, 10%).

¹H NMR Spectrum: (DMSOd₆) 1.8-2.1 (m, 4H); 3.1 (m, 2H); 3.55-3.7 (m,4H); 4.05 (s, 3H); 4.6 (t, 2H); 7.4 (m, 2H); 7.58 (d, 1H); 7.65 (dt,1H); 8.5 (s, 1H); 8.8 (s, 1H)

MS-ESI: 417 [MH]⁺ Elemental analysis: Found C 60.2 H 5.4 N 12.3C₂₁H₂₂N₄O₂ClF Requires C 60.5 H 5.3 N 13.4%

EXAMPLE 4

A solution of 1-(3-chloropropyl)pyrrolidine (230 mg, 0.96 mmol) wasadded to 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(295 mg, 0.92 mmol), (prepared as described for the starting material inExample 2), and potassium carbonate (130 mg, 0.94 mmol) in DMF (8 ml).The mixture was heated at 100° C. for 90 minutes and allowed to cool.The volatiles were removed by evaporation and the residues werepartitioned between water and methylene chloride. The organic phase wasseparated and passed through phase separating paper, and the solvent wasremoved under reduced pressure. The residue was dissolved in acetone andhydrogen chloride in ether (2 ml of a 1M solution, 2 mmol) was added.The mixture was stirred at ambient temperature for 30 minutes and theresulting precipitate was collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolinehydrochloride hydrate (320 mg, 67%).

¹H NMR Spectrum: (DMSOd₆) 1.8-2.0 (m, 6H); 3-3.6 (m, 6H); 4.05 (s, 3H);4.3 (t, 2H); 7.4 (m, 2H); 7.55 (d, 1H); 7.6 (m, 1H); 8.4 (s, 1H); 8.8(s, 1H)

MS-ESI: 431 [MH]⁺ Elemental analysis: Found C 51.0 H 5.9 N 10.6C₂₂H₂₄N₄O₂ClF 1.8H₂O 1.5HCl Requires C 51.0 H 5.7 N 10.8%

The starting material was prepared as follows:

Pyrrolidine (3 g, 42 mmol) was added to a solution of1-bromo-3-chloropropane (3.2 g, 20 mmol) in toluene (20 ml). The mixturewas stirred at ambient temperature overnight and then heated at 60° C.for 4 hours. The mixture was allowed to cool and the precipitate removedby filtration. The bulk of toluene was removed by evaporation to give anoil. ¹H NMR indicated the oil was a 1:1 mol:mol mixture of toluene and1-(3-chloropropyl)pyrrolidine. This material was used without furtherpurification.

¹H NMR Spectrum: (CDCl₃) 1.75 (m, 4H); 2.0 (q, 2H); 2.35 (s, 3H,toluene): 2.45-2.6 (m, 6H); 3.6 (t, 2H); 7.15-7.3 (m, 5H, toluene)

EXAMPLE 5

A solution of 2-(2-methoxyethoxy)ethanol (90 mg, 0.75 mmol) in methylenechloride (1 ml) was added to tributylphosphine (320 mg, 1.58 mmol) and4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.63 mmol), (prepared as described for the starting material in Example2), in methylene chloride (6 ml) at 0° C. under argon. To the resultingmixture 1,1′-(azodicarbonyl)dipiperidine (400 mg, 1.6 mmol) was added inportions. The mixture was allowed to warm to ambient temperature andstirred under argon for 2 hours. Ether (5 ml) was added, and theprecipitated solids were removed by filtration. The volatiles wereremoved from the filtrate by evaporation, and the residue was purifiedby column chromatography eluting with methylene chloride/methanol(90/10). The resulting partially purified product was dissolved inacetone, and ethereal hydrogen chloride (0.6 ml of a 1M solution, 0.6mmol) added. The resulting precipitated product was collected byfiltration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazolinehydrochloride (128 mg, 44%).

¹H NMR Spectrum: (DMSOd₆) 3.25 (s, 3H); 3.45 (dd, 2H); 3.6 (dd, 2H); 3.8(t, 2H); 4.0 (s, 3H); 4.3 (t, 2H); 7.4 (s, 1H); 7.45 (dd, 1H); 7.55-7.7(m, 2H); 8.3 (s, 1H); 8.75 (s, 1H); 11.5 (br s, 1H)

MS-ESI: 422 [MH]⁺ Elemental analysis: Found C 52.3 H 4.7 N 9.1C₂₀H₂₁N₃O₄ClF 1HCl Requires C 52.4 H 4.8 N 9.2%

EXAMPLE 6

A solution of 2-(bromomethyl)-1,3-dioxolane (190 mg, 1.1 mmol) in DMF (1ml) was added to4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (258 mg,0.81 mmol), (prepared as described for the starting material in Example2), and potassium carbonate (200 mg, 1.5 mmol) in DMF (2 ml). Themixture was heated at 100° C. for 4 hours and then allowed to cool. Thevolatiles were removed by evaporation and the residue partitionedbetween water and methylene chloride. The organic phase was separated,passed through phase separating paper and purified by columnchromatography eluting with methylene chloride/methanol (95/5) to give4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline(130 mg, 38%).

¹H NMR Spectrum: (DMSOd₆) 3.8-4.1 (m, 7H); 4.15 (d, 2H); 5.30 (t, 1H);7.22 (s, 1H); 7.30 (m, 1H); 7.55 (m, 2H); 7.80 (s, 1H); 8.35 (s, 1H);9.55 (s, 1H). Also contained 0.3 methanol.

MS-ESI: 406 [MH]⁺ Elemental analysis: Found C 55.1 H 4.5 N 9.5C₁₉H₁₇N₃O₄ClF 0.3H₂O Requires C 55.1 H 4.5 N 10.0% 0.3 Methanol

EXAMPLE 7

A mixture of 6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-one (1.75 g,7.0 mmol) and thionyl chloride (25 ml) and DMF (3 drops) was heated atreflux for 2 hours. Excess thionyl chloride was removed by evaporationand the residue azeotroped with toluene. 3-Hydroxy-4-methylaniline (0.94g, 7.6 mmol) in 2-propanol (40 ml) was added to the residue and themixture heated at reflux for 2 hours. The mixture was allowed to cool,the precipitate collected by filtration, washed with 2-propanol anddried to give6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)-5-nitroquinazolinehydrochloride (2.02 g, 81%).

m.p. 206-208° C.

¹H NMR Spectrum: (DMSOd₆) 3.90 (s, 3H); 4.05 (s, 1H); 6.50 (d, 1H); 6.65(s, 1H); 6.97 (d, 1H); 7.57 (s, 1H); 8.15 (s, 1H)

MS-ESI: 357 [MH]⁺ Elemental analysis: Found C 52.0 H 4.3 N 13.9C₁₇H₁₆N₄O₅ 1HCl Requires C 52.0 H 4.3 N 14.3%

The starting material was prepared as follows:

A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10ml) was stirred and heated at 190° C. for 5 hours. The mixture wasallowed to cool to approximately 80° C. and water (50 ml) was added. Themixture was stored at ambient temperature for 3 hours. The precipitatewas isolated, washed with water and dried to give6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).

Fuming nitric acid (47 ml) was added to6,7-dimethoxy-3,4-dihydroquinazolin-4-one (10 g, 48 mmol), in water (40ml). The reaction mixture was heated at 120° C. for 1 hour, then allowedto cool and diluted with water. The resulting precipitate was collectedby filtration, washed with water and dried to give6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-one (3.9 g, 32%).

¹H NMR Spectrum: (DMSOd₆) 3.87 (s, 3H); 4.05 (s, 1H); 7.42 (s, 1H); 8.13(s, 1H)

MS-ESI: 251 [MH]⁺

EXAMPLE 8

Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), themixture stirred for 15 minutes to give a complete solution and thevolatiles removed by evaporation. The residue was dissolved in DMSO (5ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazolinehydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred atambient temperature for 18 hours then diluted with a solution of aceticacid (1 ml) in water (20 ml). The resulting precipitate was collected byfiltration, washed with water, dried and purified by columnchromatography eluting with methylene chloride/methanol (96/4). Thepurified product was recrystallised from methylene chloride/isohexane togive 4-(4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)-6-nitroquinazoline(304 mg, 60%) as a yellow solid.

¹H NMR Spectrum: (DMSOd₆) 3.15 (s, 3H); 3.60 (m, 2H); 4.31 (m, 2H); 7.24(m, 1H); 7.4-7.5 (m, 3H); 8.42 (s, 1H); 9.03 (s, 1H)

MS-ESI: 393 [MH]⁺ Elemental analysis: Found C 51.8 H 3.7 N 14.1C₁₇H₁₄N₄O₄ClF Requires C 52.0 H 3.6 N 14.3%

The starting material was prepared as follows:

A mixture of 7-chloro-6-nitro-3,4-dihydroquinazolin-4-one (40 g, 0.18mol), (J. Org. Chem. 1975, 40, 356), phosphorus oxychloride (50 ml) andDMF (1 ml) in thionyl chloride (300 ml) was heated at reflux for 4hours. The reaction mixture was allowed to cool and the volatilesremoved by evaporation and by azeotroping with toluene. The residue wasbasified with aqueous sodium hydrogen carbonate solution and extractedwith methylene chloride (4×100 ml). The extracts were combined, washedwith brine and filtered through phase separating paper. The solvent wasremoved by evaporation and the residue triturated with ether/isohexaneto give 4,7-dichloro-6-nitroquinazoline (35.2 g, 81%) as a pale yellowsolid.

A mixture of 4,7-dichloro-6-nitroquinazoline (24.4 g, 0.1 mol),4-chloro-2-fluoroaniline and ethereal hydrogen chloride (100 ml of a 1Msolution) in 2-propanol (600 ml) was heated at reflux for 1.5 hours. Themixture was allowed to cool and diluted with acetone. The solid productwas collected by filtration, washed with acetone and dried to give7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride(35.0 g, 90%) as a yellow powder.

MS-ESI: 353 [MH]⁺

EXAMPLE 9

Triphenylphosphine (410 mg, 1.5 mmol) and 1-methyl-3-pyrrolidinol (0.128ml, 1.5 mmol) were added to a solution of4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78mmol), (prepared as described for the starting material in Example 2),in methylene chloride (4 ml). Diethyl azodicarboxylate (0.246 ml, 1.5mmol) was added dropwise and the reaction mixture was stirred for 1 hourat ambient temperature. Additional triphenylphosphine (61 mg, 0.23 mmol)followed by diethyl azodicarboxylate (37 μl, 0.23 mmol) was added andthe mixture was stirred for 15 minutes at ambient temperature. Thesolvent was removed by evaporation and the residue was purified bycolumn chromatography eluting with methylene chloride/methanol (80/20)followed by methylene chloride/methanol/triethylamine (80/20/0.5). Thepurified product was dissolved in methylene chloride/methanol and theinsolubles were removed by filtration. A solution of hydrogen chloridein 2-propanol (0.5 ml of a SM solution) was added to the filtrate andthe volatiles were removed by evaporation. The residue was trituratedwith 2-propanol and ether, collected by filtration and dried to give4-(4-chloro-2-fluoranilino)-6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazolinehydrochloride hydrate (149 mg, 40%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.13-2.83 (m, 2H); 2.92 (s, 3H); 2.99(s, 3H); 3.20-3.32 (m, 1H); 3.44-3.59 (m, 1H); 3.72-3.81 (m, 1H);3.96-4.14 (m, 2H); 4.01 (s, 3H); 5.35-5.43 (m, 1H); 7.42-7.47 (m, 2H);7.58-7.63 (m, 2H); 8.21 (s, 1H); 8.88 (s, 1H)

MS-ESI: 403 [MH]⁺ Elemental analysis: Found C 48.8 H 5.2 N 11.0C₂₀H₂₀N₄O₂ClF 1H₂O 2HCl Requires C 48.7 H 4.9 N 11.4%

EXAMPLE 10

4-(Chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78mmol), (prepared as described for the starting material in Example 2),and triphenylphosphine (512 mg, 1.9 mmol) were added to a stirredsolution of 4-morpholino-2-butyn-1-ol (182 mg, 1.1 mmol), (J. Am. Chem.Soc. 1957, 79, 6184), in methylene chloride (4 ml) under argon. Diethylazodicarboxylate (0.307 ml, 1.9 mmol) was added dropwise and thereaction mixture was stirred for 30 minutes at ambient temperature.Additional 4-morpholino-2-butyn-1-ol (60 mg, 0.39 mmol),triphenylphosphine (102 mg, 0.39 mmol) and followed by diethylazodicarboxylate (61 μl, 0.39 mmol) were added and the mixture wasstirred for a further 15 minutes at ambient temperature. The solvent wasremoved by evaporation and the residue was purified by columnchromatography eluting with methylene chloride/acetonitrile/methanol(60/37/3 followed by 60/35/5 and 55/37/8). The resulting purified oilwas dissolved in a mixture of methylene chloride and methanol andethereal hydrogen chloride (1 ml of a 2.9M solution) was added. Thevolatiles were removed by evaporation, the solid residue suspended inether and collected by filtration. The product was recrystallised from2-propanol/methanol/ether, collected by filtration, washed with2-propanol and ether and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazolinehydrochloride hydrate (75 mg, 18%).

m.p. 175-178° C.

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.10 (m, 2H); 3.46 (m, 2H); 3.72 (m,2H); 3.99 (m, 2H); 4.03 (s, 3H); 4.29 (s, 2H); 5.28 (s, 2H); 7.47 (dd,2H); 7.62 (s, 1H); 7.62 (t, 1H); 7.69 (dd, 1H); 8.29 (s, 1H); 8.89 (s,1H)

MS-ESI: 457 [MH]⁺ Elemental analysis: Found C 50.8 H 4.9 N 10.3C₂₃H₂₂N₄O₃ClF1H₂O2HCl Requires C 50.4 H 4.7 N 10.2%

EXAMPLE 11

Tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) followed bya solution of sodium triisopropylsilylthiolate (102 mg, 0.48 mmol),(Tetrahedron. Lett. 1994, 35, 3221), in THF (2 ml) was added to astirred solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline(180 mg, 0.4 mmol) in THF (2 ml) and benzene (2 ml) under argon. Thereaction mixture was heated at reflux for 2 hours and then allowed tocool. 2-Bromoethyl methyl ether (83 mg, 0.6 mmol) in DMF (1 ml) and thena solution of tetrabutylammonium fluoride in THF (0.5 ml of a 1Msolution, 0.5 mmol) were added dropwise and the reaction mixture wasstirred at ambient temperature for 30 minutes. The mixture was dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄) and thevolatiles removed by evaporation. The residue was purified by columnchromatography on neutral alumina eluting with methylenechloride/acetone (95/5). The purified product was triturated with ether,collected by filtration and dissolved in methylene chloride (4 ml).Ethereal hydrogen chloride (0.4 ml of 3M solution) was added, thesolution was diluted with ether and the resulting precipitate wascollected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethylthio)quinazolinehydrochloride (80 mg, 46%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.33 (t, 2H); 3.34 (s, 3H); 3.71 (t,2H); 4.07 (s, 3H); 7.48 (dd, 1H); 7.64 (t, 1H); 7.69 (dd, 1H); 7.73 (s,1H); 8.10 (s, 1H); 8.89 (s, 1H).

MS-ESI: 394 [MH]⁺ Elemental analysis: Found C 50.1 H 4.3 N 9.8 S 7.3C₁₈H₁₇N₃O₂ClFS1HCl Re- C 50.2 H 4.2 N 9.8 S 7.4% quires

The starting material was prepared as follows:

Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to astirred suspension of4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (959 mg, 3mmol), (prepared as described for the starting material in Example 2),in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0°C. The reaction mixture was stirred for 1 hour at 0° C. allowed to warmto ambient temperature and stirred for a further 1.5 hours. Thevolatiles were removed by evaporation, the residue was dissolved inethyl acetate, washed with dilute hydrochloric acid and brine, dried(MgSO₄) and the solvent removed by evaporation. The residue wastriturated with ether/petroleum ether to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline(270 mg, 60%) as a beige solid.

¹H NMR Spectrum: (DMSOd₆) 4.07 (s, 3H); 7.39 (dd, 1H); 7.57-7.62 (m,2H); 7.92 (s, 1H); 8.21 (s, 1H); 8.49 (s, 1H)

MS-ESI: 452 [MH]⁺

EXAMPLE 12

4-(2-Hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol), (J. Am. Chem. Soc.1934. 56, 1720), in methylene chloride (1 ml) followed by1,1′-(azodicarbonyl)dipiperidine (525 mg, 2.08 mmol) were added to astirred solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg,0.70 mmol), (prepared as described for the starting material in Example2), and tributylphosphine (0.51 ml, 2.08 mmol) in methylene chloride (10ml) under nitrogen. The mixture was stirred for 3.5 hours and allowed tostand for a further 18 hours. Ether (8 ml) was added, the precipitateremoved by filtration and the solvent removed from the filtrate byevaporation. The residue was dissolved in acetone and ethereal hydrogenchloride (2.5 ml of a 1M solution) added. The precipitated product wascollected by filtration and purified by column chromatography elutingwith methylene chloride/methanol/aqueous ammonia (150/8/1). The purifiedproduct was triturated with ether to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline(70 mg, 22%) as a pale yellow solid.

m.p. 181-182° C.

¹H NMR Spectrum: (DMSOd₆) 3.56 (t, 2H); 3.92 (s, 3H); 4.59 (t, 2H); 7.31(dd, 1H); 7.35 (s, 1H); 7.46 (d, 1H); 7.53 (dd, 1H); 8.33 (s, 1H); 8.68(s, 1H); 11.7 (br s, 1H)

MS-ESI: 449 [MH]⁺ Elemental analysis: Found C 56.4 H 5.1 N 12.3C₂₁H₂₂N₄O₂ClFS Requires C 56.2 H 4.9 N 12.5%

EXAMPLE 13

A solution of (R)-(1-methylpiperidin-3-yl)methanol (2.29 g, 18 mmol) inmethylene chloride (10 ml) was added to a stirred mixture of4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4.0 g, 12.5mmol), (prepared as described for the starting material in Example 2),and triphenylphosphine (9.81 g, 37.5 mmol) in methylene chloride (200ml). Diethyl azodicarboxylate (5.87 ml, 37 mmol) was added dropwise andthe reaction mixture was stirred for 18 hours at ambient temperature.The volatiles were removed by evaporation and the residue was purifiedby column chromatography eluting with methylenechloride/methanol/aqueous ammonia (a gradient from 100/0/0 to85/15/0.1). The purified product was triturated with ethyl acetate,collected by filtration, washed with ethyl acetate and dried to give(R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline(2.78 g, 52%).

[α]_(D) +11.7°

¹H NMR Spectrum: (DMSOd₆) 1.08 (m, 1H); 1.50 (m, 1H); 1.64 (m, 1H); 1.80(m, 3H); 2.07 (m, 1H); 2.16 (s, 3H); 2.62 (d, 1H); 2.81 (d, 1H); 3.92(s, 3H); 4.02 (d, 2H); 7.18 (s, 1H); 7.32 (d, 1H); 7.55 (m, 2H); 7.79(s, 1H); 8.34 (s, 1H); 9.50 (s, 1H)

MS-ESI: 431 [MH]⁺ Elemental analysis: Found C 60.7 H 5.4 N 13.3C₂₂H₂₄N₄O₂ClF Requires C 61.3 H 5.6 N 13.0%

The starting material was prepared as follows:

(R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by resolution of ethylnipecotate by treatment with L(+)-tartaric acid as described in J. Org.Chem. 1991, (56), 1168), was dissolved in 38.5% aqueous formaldehydesolution (45 ml) and formic acid (90 ml) and the mixture heated atreflux for 18 hours. The mixture was allowed to cool and added dropwiseto cooled saturated aqueous sodium hydrogen carbonate solution. Themixture was adjusted to pH 12 by addition of sodium hydroxide and themixture was extracted with methylene chloride. The organic extract waswashed with brine, dried (MgSO₄) and the solvent removed by evaporationto give (R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as acolourless oil.

MS-ESI: 172 [MH]

A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate (5.69 g, 33mmol) in ether (20 ml) was added dropwise to a stirred solution oflithium aluminium hydride (36.6 ml of a 1M solution in THF, 36.6 mmol)in ether (85 ml) cooled to maintain a reaction temperature of 20° C. Themixture was stirred for 1.5 hours at ambient temperature and then water(1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water(4.3 ml) were added. The insolubles were removed by filtration and thevolatiles removed from the filtrate by evaporation to give(R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless oil.

¹H NMR Spectrum: (DMSOd₆) 1.06 (q, 1H); 1.51-1.94 (m, 5H); 2.04 (s, 3H);2.34 (br s, 1H); 2.62 (m, 1H); 2.78 (d, 1H); 3.49 (m, 1H); 3.59 (m, 1H)

MS-ESI: 130 [MH]⁺

EXAMPLE 14

Using a method analogous to that in Example 13,(S)-(1-methylpiperidin-3-yl)methanol (185 g, 1.1 mmol), (prepared asdescribed for the starting material in Example 13 but resolving withD(−)-tartaric acid), was treated with4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319 mg, 1mmol), (prepared as described for the starting material in Example 2),triphenylphosphine (785 mg, 3 mmol) and diethyl azodicarboxylate (0.475ml, 3 mmol) to give, after work-up and purification,(S)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline(187 mg, 44%).

EXAMPLE 15

The final compounds in Examples 13 and 14 may be mixed, in any relativeproportions, for example to give a racemic mixture.

Alternatively the racemate may be made as follows:

1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg,0.75 mmol), (prepared as described for the starting material in Example2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) andtributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). Themixture was stirred for 18 hours, diluted with ether and the resultingprecipitate was removed by filtration. The volatiles were removed fromthe filtrate by evaporation, and the residue was dissolved in acetoneand ethereal hydrogen chloride (1.5 ml of a 1M solution, 1.5 mmol) wasadded. The precipitated product was collected by filtration and purifiedby column chromatography eluting with methylenechloride/methanol/aqueous ammonia (75/8/1).

The purified solid product was triturated with ether collected byfiltration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline(105 mg, 33%).

m.p. 211-212° C.

¹H NMR Spectrum: (DMSOd₆) 1.08 (m, 1H); 1.50 (m, 1H); 1.78 (m, 4H); 2.08(m, 1H) 2.16 (m, 3H); 2.62 (m, 1H); 2.82 (m, 1H); 3.95 (s, 3H); 4.00 (d,2H); 7.18 (s, 1H); 7.32 (m, 1H); 7.52 (dd, 1H); 7.58 (t, 1H); 7.79 (s,1H); 8.35 (s, 1H); 9.52 (s, 1H)

MS-ESI: 431 [MH]⁺ Elemental analysis: Found C 59.9 H 5.5 N 12.9C₂₂H₂₄N₄O₂ClF0.5H₂O Requires C 60.0 H 5.7 N 12.7%

EXAMPLE 16

3-(Methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol) followed by1,1′-(azodicarbonyl)dipiperidine (4.2 g, 16 mmol) in portions were addedto a stirred solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (110.5 g,4.7 mmol), (prepared as described for the starting material in Example2), and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50ml) under nitrogen. The mixture was stirred for 18 hours, the resultingprecipitate was collected by filtration and dried to give crude product(10.36 g). The solvent was removed from the filtrate by evaporation andthe residue was purified by column chromatography eluting with methylenechloride/methanol (a gradient from 100/0 to 90/10). The semi-purifiedproduct was triturated with acetone and the solid product collected byfiltration and dried to give further crude product (0.53 g). Thefiltrate from the trituration was repurified by column chromatography asbefore to give further crude product (0.23 g). The crude products werecombined and dissolved in acetone/methanol/methylene chloride andethereal hydrogen chloride (6 ml of a 1M solution) added. Theprecipitated product was collected by filtration and recrystallised frommethanol/methylene chloride/hexane to give4-(4-chloro-2-fuoroanilino)-6-methoxy-7-(3-(methylsulphonylpropoxy)quinazolinehydrochloride (640 mg, 29%).

m.p.>250° C.

¹H NMR Spectrum: (DMSOd₆) 2.25 (q, 2H); 3.02 (s, 3H); 3.36 (t, 2H); 4.00(s, 3H); 4.30 (t, 2H); 7.35 (s, 1H); 7.42 (d, 1H); 7.60 (t, 1H); 7.65(d, 1H); 8.25 (s, 1H); 8.78 (s, 1H) 11.5 (br s, 1H)

MS-ESI: 440 [MH]⁺ Elemental analysis: Found C 47.8 H 4.2 N 8.8 S 6.7C₁₉H₁₉N₃O₄ClFS1HCl Requires C 47.4 H 4.2 N 9.0 S 6.8%

The starting material was prepared as follows:

A solution of 3-(methylthio)propan-1-ol (5.3 g, 50 mmol) in methanol(500 ml) was added to a solution of OXONE, (trade mark of E.I. du Pontde Nemours & Co., Inc), (30 g) in water (150 ml) and the mixture stirredat ambient temperature for 24 hours. The precipitated solid was removedby filtration and the methanol removed from the filtrate by evaporation.The aqueous residue was saturated with sodium chloride and extractedwith methylene chloride (4×25 ml). The aqueous residue was thensaturated with ammonium chloride and extracted with ethyl acetate (4×25ml). The extracts were combined, dried (MgSO₄) and the solvent removedby evaporation to give 3-(methylsulphonyl)propan-1-ol (610 mg, 9%) as anoil.

¹H NMR Spectrum: (CDCl₃) 2.10 (m, 2H); 2.96 (s, 3H); 3.20 (t, 2H); 3.80(t, 2H)

MS-ESI: 139 [MH]⁺

EXAMPLE 17

Diethyl azodicarboxylate (5.91 ml, 37 mmol) was added dropwise to astirred mixture of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.97 g, 28mmol), 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g,9 mmol), (prepared as described for the starting material in Example 2),and triphenylphosphine (9.84 g, 38 mmol) in methylene chloride (300 ml).The reaction mixture was stirred for 18 hours at ambient temperature.The volatiles were removed by evaporation and the residue was purifiedby column chromatography eluting with methylene chloride/methanol (agradient from 80/20 to 70/30). The purified product was dissolved inmethylene chloride/methanol and 1M ethereal hydrogen chloride (25 ml)was added. The precipitated product was collected by filtration, washedwith ether and dried to give(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazolinehydrochloride (1.62 g, 33%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.85-1.95 (m, 2H); 2.0-2.15 (m, 2H);3.0-3.1 (m, 2H); 3.5-3.6 (m, 2H); 3.95 (d, 2H); 4.1 (s, 3H); 4.95 (d,2H); 6.1 (td, 1H); 6.35 (td, 1H); 7.4 (s, 1H); 7.45 (dd, 1H); 7.6-7.7(m, 2H); 8.15 (s, 1H); 8.90 (s, 1H)

MS-EI: 443 [MH]⁺ Elemental analysis: Found C 52.7 H 5.3 N 10.8C₂₁H₂₄N₄O₂ClF0.6H₂O1.85HCl Re- C 53.0 H 5.2 N 10.7% quires

The starting material was prepared as follows:

Thionyl chloride (9.3 ml, 128 mmol) was added dropwise to a stirredsolution of 2-butyne-1,4-diol (10 g, 116 mmol) in toluene (15 ml) andpyridine (10.3 ml) cooled at 0° C. The mixture was stirred for 3.5 hoursat ambient temperature and then poured onto ice water. The mixture wasextracted with ether, the organic layer was washed with saturatedaqueous sodium hydrogen carbonate solution and then brine, dried (MgSO₄)and the volatiles removed by evaporation. The residue was purified bycolumn chromatography eluting with petroleum ether/ether (7/3) to give4-chlorobut-2-yn-1-ol (4.74 g, 39%).

¹H NMR Spectrum: (CDCl₃) 1.68 (t, 1H); 4.18 (d, 2H); 4.33 (d, 2H)

Pyrrolidine (7.8 ml, 94 mmol) was added dropwise to a solution of4-chlorobut-2-yn-1-ol (4.74 g, 45 mmol) in toluene (40 ml) and themixture stirred and heated at 60° C. for 1 hour. The volatiles wereremoved by evaporation and the residue was purified by chromatographyeluting with methylene chloride/methanol (96/4) to give4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%).

¹H NMR Spectrum: (CDCl₃) 1.82 (t, 4H); 2.63 (t, 4H); 3.44 (t, 2H); 4.29(t, 2H)

A solution of 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 31 mmol) in THF(20 ml) was added dropwise to a suspension of lithium aluminium hydride(2.35 g, 62 mmol) in anhydrous THF (8 ml) and the mixture stirred andheated at 60° C. for 2 hours. The mixture was cooled to 5° C. and 2Maqueous sodium hydroxide solution (28 ml) was added dropwise. Theresulting suspension was filtered and the volatiles removed from thefiltrate by evaporation. The residue was dissolved in a mixture ofmethylene chloride/ethyl acetate, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatography onaluminum oxide eluting with methylene chloride/methanol (97/3) to give(E)-4-(pyrrolidin 1-yl)but-2-en-1-ol (3.09 g, 70%).

¹H NMR Spectrum: (CDCl₃) 1.82 (m, 4H); 2.61 (m, 4H); 3.17 (m, 2H); 4.13(s, 2H); 5.84 (m, 2H)

EXAMPLE 18

A solution of4-(4-bromo-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline(150 mg, 0.34 mmol) in 1-(2-hydroxyethyl)piperazine (5 ml) was heated at100° C. for 30 minutes. The reaction mixture was allowed to cool andmade basic with aqueous sodium hydrogen carbonate solution and extractedwith ethyl acetate (3×50 ml). The extracts were combined, washed twicewith water, then brine and dried (MgSO₄). The volatiles were removed byevaporation and the residue dissolved in acetone/methanol (10/1) (50 ml)and ethereal hydrogen chloride added. The resulting precipitate wascollected by filtration, washed with ether and hexane and dried undervacuum to give4-(bromo-2-fluoroanilino)-7-(3-[4-(2-hydroxyethyl)piperazinyl]propoxy)-6-methoxyquinazolinehydrochloride (180 mg, 80%).

¹H NMR Spectrum: (DMSOd₆) 2.35 (br t, 2H); 3.2-3.8 (br m, 1H); 3.80 (t,2H); 4.02 (s, 3H); 4.35 (t, 2H); 7.45 (s, 1H); 7.30 (s, 1H); 7.50-7.58(m, 2H); 7.76 (dd, 1H); 8.42 (s, 1H); 8.80 (s, 1H); 11.82 (br s, 1H)

MS-ESI: 534 [MH]⁺

The starting material was prepared as follows:

A mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(1.2 g, 3.3 mmol), (prepared as described for the starting material inExample 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassiumcarbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45° C. for 3hours. The mixture was allowed to cool, was diluted with water andextracted with ethyl acetate (3×70 ml). The organic extracts werecombined, washed with water and brine, dried (MgSO₄) and the volatileswere removed by evaporation. The residue was triturated withhexane/ethyl acetate, collected by filtration and dried under vacuum togive4-(4-bromo-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline(492 mg, 34%).

¹H NMR Spectrum: (DMSOd₆) 2.24 (m, 2H); 3.80 (t, 2H); 3.95 (s, 3H); 4.26(t, 2H); 7.20 (s, 1H); 7.42-7.55 (m, 2H); 7.63 (dd, 1H); 7.80 (s, 1H);8.35 (s, 1H); 9.52 (s, 1H)

MS-ESI: 440 [MH]⁺

EXAMPLE 19

A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc),(390 mg) in water (2 ml) was added to a solution of4-(chloro-2-fluoroanilino)-7-(3-(ethylthio)propoxy)-6-methoxyquinazoline(75 mg, 0.18 mmol) in methanol (10 ml) and the mixture stirred for 18hours at ambient temperature. The reaction mixture was basified withaqueous sodium hydrogen carbonate solution and extracted with ethylacetate (3×25 ml). The extracts were combined, washed twice with waterand then with brine, dried (MgSO₄) and the solvent removed byevaporation. The solid residue was recrystallised from ethylacetate/hexane to give4-(chloro-2-fluoroanilino)-7-(3-(ethylsulphonyl)propoxy)-6-methoxyquinazoline(35 mg, 43%).

¹H NMR Spectrum: (DMSOd₆) 1.24 (t, 3H); 2.22 (m, 2H); 3.15 (q, 2H); 3.95(s, 3H); 4.25 (t, 2H); 7.20 (s, 1H); 7.35 (dd, 1H); 7.5-7.6 (m, 2H);7.80 (s, 1H); 8.35 (s, 1H); 9.54 (s, 1H)

MS-ESI: 454 [MH]⁺ Elemental analysis: Found C 51.7 H 4.6 N 9.2C₂₀H₂₁N₃O₄ClFS0.5H₂0 Requires C 51.9 H 4.8 N 9.1%

The starting material was prepared as follows:

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(957 mg, 3 mmol), (prepared as described for the starting material inExample 2), 1-bromo-3-chloropropane (2.36 g, 15 mmol) and potassiumcarbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40° C. for 1.5hours. The mixture was allowed to cool, was diluted with water andextracted with ethyl acetate (3×50 ml). The organic extracts werecombined, washed with water and brine, dried (MgSO₄) and the volatileswere removed by evaporation. The residue was triturated withhexane/ethyl acetate, collected by filtration and dried under vacuum togive4-(4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline(650 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 2.26 (m, 2H); 3.82 (t, 2H); 3.95 (s, 3H); 4.26(t, 2H); 7.20 (s, 1H); 7.32 (dd, 1H); 7.48-7.60 (m, 2H); 7.80 (s, 1H);8.35 (s, 1H); 9.52 (s, 1H)

MS-EI: 396 [MH]⁺

A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and4-(4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline(227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for3 hours. The reaction mixture was allowed to cool, was diluted withwater and extracted with ethyl acetate (3×75 ml). The extracts werecombined, washed with water (×2), and then brine, and dried (MgSO₄). Thesolvent was removed by evaporation and the residue was recrystallisedfrom ethyl acetate/hexane to give4-(chloro-2-fluoroanilino)-7-(3-(ethylthio)propoxy)-6-methoxyquinazoline(86 mg, 40%).

¹H NMR Spectrum: (DMSOd₆) 1.20 (t, 3H); 2.03 (m, 2H); 2.66 (t, 2H); 3.95(s, 3H); 4.20 (t, 2H); 7.18 (s, 1H); 7.33 (dd, 1H); 7.5-7.6 (m, 2H);7.78 (s, 1H); 8.35 (s, 1H); 9.52 (s, 1H)

MS-ESI: 422 [MH]⁺

EXAMPLE 20

A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(3.28 g, 10 mmol), (prepared as described for the starting material inExample 2), 1-bromo-3-tetrahydropyranyloxypropane (2.5 g, 11 mmol) andpotassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred andheated at 90° C. for 3 hours. The reaction mixture was allowed to cool,was diluted with water (500 ml) and extracted with ethyl acetate (3×100ml). The extracts were combined, washed with water (×3), and then brine,and dried (MgSO₄). The solvent was removed by evaporation and theresidue was purified by column chromatography eluting with ethylacetate. The purified product was recrystallised from ethylacetate/hexane to give4-(chloro-2-fluoroanilino)-6-methoxy-7-(3-tetrahydropyran-2-yloxypropoxy)quinazoline(2.25 g, 49%).

m.p. 184-185° C.

¹H NMR Spectrum: (DMSOd₆) 1.35-1.54 (m, 4H); 1.55-1.75 (m, 2H); 2.05 (m,2H); 3.35-3.45 (m, 1H); 3.66-3.84 (m, 2H); 3.95 (s, 3H); 4.23 (t, 2H);4.60 (s, 1H); 7.18 (s, 1H); 7.32 (dd, 1H); 7.5-7.6 (m, 2H); 7.78 (s,1H); 8.35 (s, 1H); 9.53 (s, 1H)

MS-ESI: 462 [MH]⁺ Elemental analysis: Found C 59.6 H 5.3 N 9.1C₂₃H₂₅N₃O₄ClF Requires C 59.9 H 5.4 N 9.4%

EXAMPLE 21

A mixture of sodium methanethiolate (70 mg, 1 mmol) and4-(4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline(200 mg, 0.5 mmol), (prepared as described for the starting material inExample 19), in DMF (10 ml) was stirred and heated at 70° C. for 1 hour.The reaction mixture was allowed to cool, was diluted with water andextracted with ethyl acetate (3×25 ml). The extracts were combined,washed with water (×2), and then brine, and dried (MgSO₄). The solventwas removed by evaporation and the residue was recrystallised from ethylacetate/hexane to give4-(chloro-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline(143 mg, 35%).

m.p. 169-170° C.

¹H NMR Spectrum: (DMSOd₆) 2.0-2.12 (m, 2H); 2.08 (s, 3H); 2.64 (t, 2H);3.93 (s, 3H); 4.21 (t 2H); 7.18 (s, 1H); 7.33 (d, 1H); 7.50-7.61 (m,2H); 7.78 (s, 1H); 8.34 (s, 1H); 9.53 (s, 1H)

MS-ESI: 408 [MH]⁺

EXAMPLE 22

A mixture of 4-(bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(250 mg, 0.7 mmol), (prepared as described for the starting material inExample 48), 2-chloroethyl methyl sulphide (0.1 ml, 1 mmol) andpotassium carbonate (11.0 g, 7 mmol) in DMF (10 ml) was stirred andheated at 50° C. for 4 hours. The reaction mixture was allowed to cool,was diluted with water and extracted with ethyl acetate (3×25 ml). Theextracts were combined, washed with water (×2), and then brine, anddried (MgSO₄). The solvent was removed by evaporation and the residuewas purified by column chromatography eluting with ethyl acetate. Thepurified product was recrystallised from ethyl acetate/hexane to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline(100 mg, 34%).

¹H NMR Spectrum: (DMSOd₆) 2.20 (s, 3H); 2.90 (t, 2H); 3.92 (s, 3H); 4.30(t, 2H); 7.20 (s, 1H); 7.42-7.54 (m, 2H); 7.62 (dd, 1H); 7.80 (s, 1H);8.36 (s, 1H); 9.54 (s, 1H)

MS-ESI: 438 [MH]⁺ Elemental analysis: Found C 48.8 H 3.9 N 9.8 S 7.3C₁₈H₁₇N₃O₂BrFS Requires C 49.3 H 3.9 N 9.6 S 7.3%

EXAMPLE 23

A solution of7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (130mg, 0.36 mmol), (prepared as described for the starting material inExample 62), in 1-ethoxycarbonylpiperazine (1.5 ml) was stirred andheated at 100° C. for 2 hours. The mixture was allowed to cool, dilutedwith water and extracted with ethyl acetate (3×25 ml). The extracts werecombined, washed with water (×2) and then brine, and dried (MgSO₄). Thesolvent was removed by evaporation and the residue was dissolved inacetone and 1M ethereal hydrogen chloride (2 ml) was added. Theresulting precipitate was collected by filtration and then purified bycolumn chromatography eluting with methylene chloride/methanol/aqueousammonia (94/5/1). The purified product was dissolved in acetone and 1Methereal hydrogen chloride (2 ml) was added. The resulting precipitatewas collected by filtration, washed with ether and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-(4-ethoxycarbonylpiperazin-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (85 mg 46%).

¹H NMR Spectrum: (DMSOd₆) 1.20 (t, 3H); 3.1-3.6 (m, 8H); 3.66 (br s,2H); 4.00 (s, 3H); 4.08 (q, 2H); 4.65 (br s, 2H); 7.40 (m, 2H); 7.90 (t,1H); 7.65 (dd, 1H); 8.40 (s, 1H); 8.80 (s, 1H); 11.66 (br s, 1H)

MS-ESI: 504 [MH]⁺ Elemental analysis: Found C 48.6 H 5.0 N 12.2C₂₄H₂₇N₅O₄ClF 1H₂O 2HCl Requires C 48.5 H 5.2 N 11.8%

EXAMPLE 24

A mixture of 4-(bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(306 mg, 0.84 mmol), (prepared as described for the starting material inExample 48), 2-chloroethyl ethyl sulphide (0.15 m], 1.3 mmol) andpotassium carbonate (0.5 g, 3.6 mmol) in DMF (10 ml) was stirred andheated at 50° C. for 1 hour. The reaction mixture was allowed to cool,was diluted with water and extracted with ethyl acetate (3×25 ml). Theextracts were combined, washed with water (×2), and then brine, anddried (MgSO₄). The solvent was removed by evaporation and the residuewas purified by column chromatography eluting with ethyl acetate. Thepurified product was recrystallised from ethyl acetate/hexane to give4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline(221 mg, 58%).

¹H NMR Spectrum: (DMSOd₆) 1.24 (t, 3H); 2.66 (q, 2H); 2.94 (t, 2H); 3.95(s, 3H); 4.30 (t, 2H); 7.20 (s, 1H); 7.45 (t, 1H); 7.52 (d, 1H); 7.65(dd, 1H); 7.80 (s, 1H); 9.55 (s, 1H)

MS-ESI: 452 [MH]⁺

EXAMPLE 25

A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc),(150 mg) in water (2 ml) was added to a solution of4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline(125 mg, 0.28 mmol), (prepared as described in Example 24), in methanol(10 ml). The reaction mixture was stirred for 16 hours at ambienttemperature, the methanol was removed by evaporation, the aqueousresidue was basified with sodium hydrogen carbonate solution and thenextracted with ethyl acetate (3×30 ml). The extracts were combined,washed with water (×2), and then brine, and dried (MgSO₄). The solventwas removed by evaporation and the residue was purified by columnchromatography eluting with ethyl acetate and then with methylenechloride/methanol (9/1) to give4-(4-bromo-2-fluoroanilino)-7-(2-ethylsulphinylethoxy)-6-methoxyquinazoline(32 mg, 31%).

¹H NMR Spectrum: (DMSOd₆) 1.21 (t, 3H); 2.72-2.84 (m, 1H); 2.86-20.96(m, 1H); 3.04-3.12 (m, 1H); 3.94 (s, 3H); 4.42-4.58 (m, 2H); 7.26 (s,1H); 7.42-7.55 (m, 2H); 7.64 (dd, 1H); 7.82 (s, 1H); 8.35 (s, 1H); 9.55(s, 1H)

MS-ESI: 468 [MH]⁺

EXAMPLE 26

Using a method analogous to that in Example 25,4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline(250 mg, 0.6 mmol), (prepared as described in Example 21), was treatedwith OXONE, (trade mark of E.I. du Pont dc Nemours & Co., Inc). (84 mg)and the product was purified and isolated to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylsulphinylpropoxy)quinazoline(75 mg, 29%).

¹H NMR Spectrum: (DMSOd₆) 2.18 (t, 2H); 2.60 (s, 3H); 2.78-2.98 (m, 2H);3.95 (s, 3H); 4.25 (t, 2H); 7.20 (s, 1H); 7.35 (dd, 1H); 7.50-7.61 (m,2H); 7.80 (s, 1H); 8.53 (s, 1H); 9.55 (s, 1H)

MS-ESI: 424 [MH]⁺ Elemental analysis: Found C 53.4 H 4.5 N 9.8C₁₉H₁₉N₃O₄ClFS Requires C 53.9 H 4.5 N 9.8%

EXAMPLE 27

A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc),(800 mg) in water (3 ml) was added to a solution of4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline(320 mg, 0.7 mmol), (prepared as described in Example 24), in methanol(10 ml). The reaction mixture was stirred for 20 hours at ambienttemperature, the methanol was removed by evaporation, the aqueousresidue was basified with sodium hydrogen carbonate solution, saturatedwith sodium chloride and then extracted with ethyl acetate (3×50 ml).The extracts were combined, dried (MgSO₄) and the solvent was removed byevaporation. The residue was dissolved in acetone/methanol and 1Methereal hydrogen chloride (2 ml) was added. The volatiles were removedby evaporation, the residue was triturated with 2-propanol/hexane,collected by filtration and dried to give4-(4-bromo-2-fluoroanilino)-7-(2-ethylsulphonylethoxy)-6-methoxyquinazolinehydrochloride (200 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 1.28 (t, 3H); 3.25 (q, 2H); 3.74 (t, 2H); 4.00(s, 3H); 4.54 (t, 2H); 7.43 (s, 1H); 7.54 (m, 1H); 7.56 (s, 1H); 7.75(d, 1H); 8.36 (s, 1H); 8.78 (s, 1H); 11.61 (br s, 1H)

MS-ESI: 484 [MH]⁺

EXAMPLE 28

A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co. Inc),(800 mg) in water (3 ml) was added to a solution of4-(4-chloro-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline(220 mg, 0.56 mmol) in methanol (10 ml). The reaction mixture wasstirred for 20 hours at ambient temperature, the methanol was removed byevaporation, the aqueous residue was basified with sodium hydrogencarbonate solution, saturated with sodium chloride and then extractedwith ethyl acetate (3×50 ml). The extracts were combined, dried (MgSO₄)and the solvent was removed by evaporation. The residue was dissolved inacetone/methanol and 1M ethereal hydrogen chloride (1.2 ml) was added.The volatiles were removed by evaporation, the residue was trituratedwith 2-propanol, collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-ethylsulphonylethoxy)-6-methoxyquinazolinehydrochloride (24 mg, 9%).

¹H NMR Spectrum: (DMSOd₆) 1.25 (t, 3H); 3.30 (q, 2H); 3.75 (t, 2H); 4.00(s, 3H); 4.55 (t, 2H); 7.36 (s, 1H); 7.41 (dd, 1H); 7.58 (t, 1H); 7.64(dd, 1H); 8.22 (s, 1H); 8.78 (s, 1H)

MS-ESI: 440 [MH]⁺

The starting material was prepared as follows:

A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(450 mg, 1.4 mmol), (prepared as described for the starting material inExample 2), 2-chloroethyl ethyl sulphide (0.2 ml, 1.7 mmol) andpotassium carbonate (1.5 g, 11 mmol) in DMF (10 ml) was stirred andheated at 50° C. for 2 hours. The reaction mixture was allowed to cool,was diluted with water and extracted with ethyl acetate (3×50 ml). Theextracts were combined, washed with 0.1M sodium hydroxide solution (×2),water and then brine, and dried (MgSO₄). The solvent was removed byevaporation to give crude4-(4-chloro-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline(230 mg, 57%) which was used directly.

EXAMPLE 29

A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(400 mg, 1.3 mmol), (prepared as described for the starting material inExample 2), 2-chloroethyl methyl sulphide (0.168 ml, 1.7 mmol) andpotassium carbonate (347 mg, 2.5 mmol) in NMP (10 ml) was stirred andheated at 90° C. for 1 hour, then allowed to cool and stirred for 16hours at ambient temperature. The reaction mixture was diluted withwater and extracted with ethyl acetate. The extracts were combined,washed with water, and then brine, and dried (MgSO₄). The solvent wasremoved by evaporation, the residue was triturated with ethylacetate/hexane and collected by filtration to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline(220 mg, 44%).

m.p. 174-176° C.

¹H NMR Spectrum: (DMSOd₆) 2.20 (s, 3H); 2.92 (t, 2H); 3.94 (s, 3H); 4.32(t, 2H); 7.20 (s, 1H); 7.32 (d, 1H); 7.49-7.6 (m, 2H); 7.80 (s, 1H);8.36 (s, 1H); 9.55 (s, 1H)

MS-ESI: 452 [MH]⁺

EXAMPLE 30

A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc),(652 mg) in water (1.6 ml) was added to a solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline(200 mg, 0.5 mmol), (prepared as described in Example 29), in methanol(10 ml) and the mixture was stirred for 18 hours at ambient temperature.The mixture was diluted with methylene chloride, was washed with aqueoussodium hydrogen carbonate solution, dried (MgSO₄) and the solvent wasremoved by evaporation. The residue was triturated with ethylacetate/hexane, collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylsulphonylethoxy)quinazoline(172 mg, 80%).

m.p. 227-230° C.

¹H NMR Spectrum: (DMSOd₆) 3.18 (s, 3H); 3.70 (t, 2H); 3.92 (s, 3H); 4.50(t, 2H); 7.22-7.38 (m, 2H); 7.42 (s, 1H); 7.48-7.60 (m, 2H); 8.37 (s,1H); 9.55 (s, 1H)

MS-ESI: 426 [MH]⁺ Elemental analysis: Found C 46.0 H 3.6 N 8.7C₁₈H₁₇N₃O₄ClFS 2.2H₂O Requires C 46.4 H 4.1 N 9.0%

EXAMPLE 31

1,1′-(Azodicarbonyl)dipiperidine (1.56 g, 6.2 mmol) followed by3-(methylthio)-1-propanol (0.32 ml, 3 mmol) was added to a mixture of4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0mmol), (prepared as described for the starting material in Example 48),and tributylphosphine (1.42 ml, 6.1 mmol) in methylene chloride (20 ml)at 5° C. The mixture was stirred at 5° C. for 1 hour and then for 18hours at ambient temperature. The insolubles were removed by filtrationand the volatiles were removed from the filtrate by evaporation. Theresidue was purified by column chromatography eluting with ethylacetate/methanol (100/0 increasing to 95/5) to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline(400 mg, 50%).

m.p. 250-252° C.

¹H NMR Spectrum: (DMSOd₆) 2.08 (t, 2H); 2.64 (t, 2H); 4.00 (s, 3H); 4.28(t, 2H); 7.40 (s, 1H); 7.48-7.58 (m, 2H); 7.78 (d, 1H); 8.30 (s, 1H);8.80 (s, 1H)

MS-ESI: 452 [MH]⁺

EXAMPLE 32

A solution of OXONE, (trade mark of E.I. du Pont dc Nemours & Co., Inc),(800 mg) in water (4.5 ml) was added to a solution of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline(300 mg, 0.66 mmol), (prepared as described in Example 31), in methanol(15 ml) and the mixture was stirred for 4 hours at ambient temperature.The mixture was diluted with methylene chloride, was washed with aqueoussodium hydrogen carbonate solution, dried (MgSO₄) and the solvent wasremoved by evaporation. The residue was triturated with ethylacetate/hexane, collected by filtration and dried to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline(235 mg, 73%).

m.p.>250° C.

¹H NMR Spectrum: (DMSOd₆) 2.30 (t, 2H); 3.20 (s, 3H); 3.30 (t, 2H); 4.10(s, 3H); 4.30 (t, 2H); 7.38 (s, 1H); 7.5-7.6 (m, 2H); 7.78 (d, 1H); 8.30(s, 1H); 8.80 (s, 1H)

MS-ESI: 484 [MH]⁺ Elemental analysis: Found C 42.8 H 3.8 N 7.8C₁₉H₁₉N₃O₄BrFS 0.5H₂O Requires C 43.1 H 3.9 N 7.9%

EXAMPLE 33

1,1′-(Azodicarbonyl)dipiperidine (355 mg, 1.4 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (150 mg,0.47 mmol), (prepared as described for the starting material in Example2), 2-(cyclopentyloxy)ethanol (91 mg, 0.7 mmol), (U.S. Pat. No.4,515,814), and tributylphosphine (284 mg, 1.4 mmol) in methylenechloride (6 ml) at 0° C. The mixture was then allowed to warm to ambienttemperature and stirred for 3.5 hours. Ether (3 ml) was added and theinsolubles were removed by filtration and the volatiles were removedfrom the filtrate by evaporation. The residue was dissolved in acetoneand 1M ethereal hydrogen chloride (0.6 ml) was added. The mixture wasleft to stand for 60 hours and the precipitate was collected byfiltration, washed with acetone and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-cyclopentyloxyethoxy)-6-methoxyquinazolinehydrochloride (130 mg, 60%).

¹H NMR Spectrum: (DMSOd₆) 1.4-1.8 (m, 8H); 3.75 (t, 2H); 4.00 (s, 4H);4.30 (t, 2H); 7.37 (s, 1H); 7.42 (dd, 1H); 7.60 (t, 1H); 7.64 (dd, 1H);8.25 (s, 1H); 8.78 (s, 1H)

MS-ESI: 432 [MH]⁺ Elemental analysis: Found C 55.8 H 5.0 N 8.8C₂₂H₂₃N₃O₃ClF 1H₂O 1HCl Requires C 56.0 H 5.2 N 8.9%

EXAMPLE 34

Diethyl azodicarboxylate (0.94 ml, 6 mmol) was added dropwise to amixture of triphenylphosphine (1.57 g, 6 mmol),4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2mmol), (prepared as described for the starting material in Example 2),and N-(tert-butoxycarbonyl)ethanolamine (0.354 g, 2.2 mmol) in methylenechloride (20 ml) at 0° C. The reaction mixture was allowed to warm toambient temperature and stirred for 4 hours. The reaction mixture wasdiluted with methylene chloride, washed with aqueous sodium hydrogencarbonate solution, water and then brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol/aqueous ammonia(100/8/1). The product was recrystallised from acetonitrile, collectedby filtration, washed with ethyl acetate and dried to give7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(235 mg, 25%).

m.p. 190-191° C.

¹H NMR Spectrum: (DMSOd₆) 1.36 (s, 9H); 3.34 (q, 2H); 3.91 (s, 3H); 4.15(t, 2H); 6.98 (t, 1H); 7.19 (s, 1H); 7.33 (dd, 1H); 7.56 (m, 2H); 7.78(s, 1H); 8.34 (s, 1H); 9.51 (s, 1H)

MS-ESI: 463 [MH]⁺ Elemental analysis: Found C 57.0 H 5.1 N 12.5C₂₂H₂₄N₄O₄ClF Requires C 57.1 H 5.1 N 12.1%

EXAMPLE 35

Sodium hydride (55 mg of a 60% dispersion in mineral oil, 1.1 mmol) wasadded to a solution of glutarimide (120 mg, 1.06 mmol) in DMF (5 ml) atambient temperature under argon and the mixture stirred for 30 minutes.7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (428mg, 1 mmol), (prepared as described for the starting material in Example62), in DMF (2 ml) was added and the resulting pale green solution wasstirred for 18 hours and then quenched with water. The volatiles wereremoved by evaporation, and the residue was partitioned between waterand ethyl acetate. The organic phase was separated and washed with waterand then dried (MgSO₄). The solvent was removed by evaporation, and theresidue was purified by column chromatography eluting with ethyl acetatethen ethyl acetate/methanol (9/1). The purified product wasrecrystallised from ethyl acetate and hexane, collected by filtrationand washed with ether to give4-(4-chloro-2-fluoroanilino)-7-(2-(2,6-dioxopiperidino)ethoxy)-6-methoxyquinazoline(252 mg, 55%).

m.p. 202-203° C.

¹H NMR Spectrum: (DMSOd₆) 1.84 (m, 2H); 2.63 (t, 4H); 3.91 (s, 3H); 4.08(t, 2H); 4.17 (t, 2H); 7.10 (s, 1H); 7.34 (dd, 1H); 7.55 (m, 2H); 7.79(s, 1H); 8.34 (s, 1H); 9.52 (s, 1H)

MS-ESI: 459 [MH]⁺ Elemental analysis: Found C 57.2 H 4.2 N 11.9C₂₂H₂₀N₄O₄ClF Requires C 57.6 H 4.3 N 12.2%

EXAMPLE 36

Isobutyl chloroformate (88 mg, 5.9 mmol) was added to a stirred solutionof 7-(3-aminopropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinetrifluoroacetate (151 mg, 0.4 mmol) and triethylamine (0.2 ml, 1.4 mmol)in THF (15 ml). The reaction mixture was stirred at ambient temperaturefor 30 minutes and the volatiles were removed by evaporation. Theresidue was dissolved in methylene chloride, the solution was washedwith aqueous sodium hydrogen carbonate solution and then brine, dried(MgSO₄) and the solvent was removed by evaporation. The residue wasrecrystallised from acetonitrile to give4-(4-chloro-2-fluoroanilino)-7-(3-[N-isobutoxycarbonylamino]propoxy)-6-methoxyquinazoline(41.2 mg, 20%) as a white solid.

m.p. 136-137° C.

¹H NMR Spectrum: (DMSOd₆) 0.87 (d, 6H); 1.80 (m, 1H); 1.93 (t, 2H); 3.16(q, 2H); 3.71 (d, 2H); 3.94 (s, 3H); 4.15 (t, 2H); 7.16 (s, 2H); 7.32(dd, 1H); 7.55 (m, 2H); 7.79 (s, 1H); 8.34 (s, 1H); 9.50 (s, 1H)

MS-ESI: 477 [MH]⁺ Elemental analysis: Found C 57.1 H 4.9 N 11.6C₂₃H₂₆N₄O₄ClF Requires C 57.1 H 5.5 N 11.6%

The starting material was prepared as follows:

A solution of di-tert-butyl dicarbonate (32 g, 148 mmol) in methylenechloride (70 ml) was added dropwise to a stiffed solution of3-amino-1-propanol (10.1 g, 134 mmol) in methylene chloride (100 ml).The reaction mixture was stirred overnight and was then washed withsaturated aqueous sodium hydrogen carbonate solution, water and thenbrine. The organic layer was dried (MgSO₄) and the volatiles wereremoved by evaporation to give3-(N-tert-butoxycarbonylamino)-(N-propanol (23.3 g, 100%) as acolourless oil.

¹H NMR Spectrum: (CDCl₃) 1.48 (s, 9H); 1.68 (m, 2H); 2.90 (br s, 1H);3.30 (m, 2H); 3.65 (m, 2H); 4.78 (br s, 1H)

MS-ESI: 176 [MH]⁺

Triphenylphosphine (2.46 g, 9.3 mmol) was added to a suspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3.1mmol), (prepared as described for the starting material in Example 2),in methylene chloride (25 ml) and the suspension stirred at OIC for 30minutes. A solution of 3-(N-tert-butoxycarbonylamino)-1-propanol (0.65g, 3.7 mmol) in methylene chloride (3 ml) was added and then diethylazodicarboxylate (1.47 ml, 7.6 mmol) was added dropwise. The reactionmixture was allowed to warm to ambient temperature and stirred for 1 ghours. The reaction mixture was diluted with methylene chloride andwashed with aqueous sodium hydrogen carbonate solution, water and thenbrine. The resultant solution was dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol/triethylamine (100/0/0 and then95/4/1) to give7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(620 mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 1.36 (s, 9H); 1.89 (t, 2H); 3.11 (q, 2H); 3.91(s, 3H); 4.14 (t, 2H); 6.89 (m, 1H); 7.16 (s, 1H); 7.31 (dd, 1H); 7.56(m, 2H); 7.77 (s, 1H); 8.32 (s, 1H); 9.51 (s, 1H)

MS-ESI: 477 [MH]⁺

7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(610 mg, 1.28 mmol) was added slowly to TFA (10 ml). The reaction wasstirred at ambient temperature for 2 hours and the volatiles wereremoved by evaporation and by azeotroping with toluene to give7-(3-aminopropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinetrifluoroacetate (455 mg, 94%) as an oil.

EXAMPLE 37

A mixture of7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (425mg, 1 mmol), (prepared as described for the starting material in Example62), and 1-methyl-4-(methylamino)piperidine (128 mg, 1 mmol) inN,N-dimethylacetamide (2 ml) was stirred at 65° C. for 3 hours. Thevolatiles were removed by evaporation and the residue was purified bycolumn chromatography eluting with methylene chloride/methanol/aqueousammonia (75/8/1). The purified product was triturated with ether,collected by filtration, washed with ether and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-(1-methylpiperidin-4-yl)]amino)ethoxy)quinazoline(180 mg, 38%) as a pale yellow powder.

m.p. 191-192° C.

¹H NMR Spectrum: (DMSOd₆) 1.44 (m, 2H); 1.70 (m, 2H); 1.86 (m, 2H); 2.15(s, 3H); 2.30 (s, 3H); 2.78 (m, 2H); 2.88 (t, 2H); 3.94 (s, 3H); 4.18(t, 2H); 7.19 (s, 1H); 7.33 (m, 1H); 7.52 (m, 1H); 7.58 (t, 1H); 7.78(s, 1H); 8.34 (s, 1H); 9.48 (s, 1H)

MS-ESI: 474 [MH]⁺ Elemental analysis: Found C 60.9 H 6.3 N 14.7C₂₄H₂₉N₅O₂ClF Requires C 60.8 H 6.2 N 14.8%

EXAMPLE 38

1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg,0.75 mmol), (prepared as described for the starting material in Example2), tetrahydro-3-furanmethanol (90 mg, 0.88 mmol) and tributylphosphine(440 mg, 2.2 mmol) in methylene chloride (12 ml) and the mixture stirredfor 18 hours. The mixture was diluted with ether, and the resultingprecipitate was removed by filtration. The solvent was removed from thefiltrate by evaporation, and the residue was dissolved in acetone andethereal hydrogen chloride (0.75 ml of a 1M solution, 0.75 mmol) wasadded. The mixture was diluted with ether and the resulting precipitatewas collected by filtration. The solid was purified by columnchromatography eluting with methylene chloride/acetonitrile/methanol (agradient from 50/50/1 to 50/50/2). The purified product was trituratedwith ether, collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(tetrahydrofuran-3-ylmethoxy)quinazoline(93 mg, 31%).

m.p. 201-202° C.

¹H NMR Spectrum: (DMSOd₆) 1.70 (m, 1H); 2.05 (m, 1H); 2.72 (m, 1H); 3.56(m, 1H); 3.66 (q, 1H); 3.79 (m, 2H); 3.94 (s, 3H); 4.08 (m, 2H); 7.20(s, 1H); 7.32 (m, 1H); 7.52 (dd, 1H); 7.58 (t, 1H); 7.78 (t, 1H); 8.35(s, 1H); 9.52 (s, 1H)

MS-ESI: 404 [MH]⁺ Elemental analysis: Found C 59.2 H 4.6 N 10.6C₂₀H₁₉N₃O₃ClF Requires C 59.5 H 4.7 N 10.4%

EXAMPLE 39

1,1′-(Azodicarbonyl)dipiperidine (5.6 g, 22 mmol) was added in portionsto a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2.4 g, 7.5mmol), (prepared as described for the starting material in Example 2),tributylphosphine (4.4 g, 22 mmol) and1-(2-hydroxyethyl)-2-pyrrolidinone (1.1 g, 8.5 mmol) in methylenechloride (105 ml). The mixture was stirred for 18 hours, diluted withether (100 ml) and the resulting precipitate was removed by filtration.The volatiles were removed from the filtrate by evaporation, and theresidue was dissolved in acetone and ethereal hydrogen chloride (15 mlof a 1M solution, 15 mmol) was added. The solid was collected byfiltration and was purified by column chromatography eluting withmethylene chloride/methanol/aqueous ammonia (150/8/1). The purifiedproduct was dissolved in acetone and ethereal hydrogen chloride (15 mlof a 1M solution, 15 mmol) was added. The resulting precipitate wascollected by filtration, washed with ether and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazolinehydrochloride (2.1 g, 60%).

m.p. 250-252° C.

¹H NMR Spectrum: (DMSOd₆) 1.92 (m, 2H); 2.22 (t, 2H); 3.52 (t, 2H); 3.68(t, 2H); 4.02 (s, 3H); 4.30 (t, 2H); 7.38 (s, 1H); 7.42 (m, 1H); 7.58(t, 1H); 7.66 (dd, 1H); 8.35 (s, 1H); 8.79 (s, 1H); 11.69 (br s, 1H)

MS-ESI: 431 [MH]⁺ Elemental analysis: Found C 53.5 H 4.4 N 12.2C₂₁H₂₀N₄O₃ClF0.1H₂O1HCl Requires C 53.8 H 4.6 N 11.9%

EXAMPLE 40

1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0mmol), (prepared as described for the starting material in Example 2),tributylphosphine (420 mg, 2.1 mmol) and1-(2-hydroxyethyl)-2-imidazolidinone (100 mg, 7.7 mmol) in methylenechloride (10 ml). The mixture was stirred for 18 hours, diluted withether and the resulting precipitate was removed by filtration. Thevolatiles were removed from the filtrate by evaporation and the residuewas purified by column chromatography eluting with methylenechloride/methanol/aqueous ammonia (150/8/1). The purified product wastriturated with ether collected by filtration, washed with ether anddried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxoimidazolidin-1-yl)ethoxy)quinazoline(19 mg, 6%).

m.p.>250° C.

¹H NMR Spectrum: (DMSOd₆) 3.27 (t, 2H); 3.53 (m, 4H); 3.97 (s, 3H); 4.27(t, 2H); 6.39 (s, 1H); 7.26 (s, 1H); 7.35 (m, 1H); 7.57 (dd, 1H); 7.61(t, 1H); 7.82 (s, 1H); 8.38 (s, 1H); 9.55 (s, 1H)

MS-ESI: 432 [MH]⁺ Elemental analysis: Found C 53.7 H 4.4 N 15.4C₂₀H₁₉N₅O₃ClF1H₂O Requires C 53.4 H 4.7 N 15.6%

EXAMPLE 41

1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0mmol), (prepared as described for the starting material in Example 2),tributylphosphine (420 mg, 2.1 mmol) and4-(2-hydroxyethyl)-1,1-dioxothiomorpholine (140 mg, 7.8 mmol) inmethylene chloride (10 ml). The mixture was stirred for 18 hours,diluted with ether and the resulting precipitate was removed byfiltration. The volatiles were removed from the filtrate by evaporation,and the residue was dissolved in acetone and ethereal hydrogen chloride(14 ml of a 1M solution, 14 mmol) and the precipitate was collected byfiltration. The residue was purified by column chromatography elutingwith methylene chloride/methanol/aqueous ammonia (150/8/1). The purifiedproduct was triturated with ether/methylene chloride collected byfiltration and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-(1,1-dioxothiomorpholino)ethoxy)-6-methoxyquinazoline(120 mg, 36%).

m.p. 246-249° C.

¹H NMR Spectrum: (DMSOd₆) 3.03 (t, 2H); 3.10 (br s, 8H); 3.95 (s, 3H);4.27 (t, 2H); 7.24 (s, 1H); 7.38 (m, 1H); 7.53 (dd, 1H); 7.58 (t, 1H);7.80 (s, 1H); 8.35 (s, 1H); 9.52 (s, 1H)

MS-ESI: 481 [MH]⁺ Elemental Found C 52.0 H 4.6 N 11.9 S 6.6 analysis:C₂₁H₂₂N₄O₄ClFS Requires C 52.4 H 4.6 N 11.6 S 6.7%

EXAMPLE 42

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 4.9mmol) was added to a mixture of7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(164 mg, 0.4 mmol), morpholine (0.11 g, 1.26 mmol) and4-dimethylaminopyridine (200 mg, 1.64 mmol) in DMF (5 ml). The reactionmixture was stirred at ambient temperature for 24 hours and thevolatiles were removed by evaporation. Water was added to the residueand the aqueous mixture was extracted with methylene chloride (3×30 ml).The extracts were combined and the solvent removed by evaporation. Theresidue was triturated with ether and the precipitate was collected byfiltration. The solid was purified by column chromatography eluting withmethylene chloride/methanol/aqueous ammonia (100/8/1). The purifiedproduct was triturated with acetone, collected by filtration and driedto give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinocarbonylpropoxy)quinazoline(88 mg, 46%).

m.p. 216-217° C.

¹H NMR Spectrum: (DMSOd₆) 2.02 (m, 2H); 2.5 (m, 2H); 3.45 (m, 4H); 3.55(m, 4H); 3.92 (s, 3H); 4.15 (t, 2H); 7.18 (s, 1H); 7.32 (d, 1H); 7.55(m, 2H); 7.78 (s, 1H); 8.34 (s, 1H); 9.52 (s, 1H)

MS-ESI: 475 [MH]⁺ Elemental analysis: Found C 58.2 H 5.2 N 12.2C₂₃H₂₄N₄O₄ClF Requires C 58.2 H 5.1 N 11.8%

The starting material was prepared as follows:

Ethyl 4-chlorobutyrate (0.154 ml, 1.1 mmol) was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1mmol), (prepared as described for the starting material in Example 2),and anhydrous potassium carbonate (690 mg, 5 mmol) in DMF (10 ml). Themixture was stirred and heated at 105° C. for 4 hours then allowed tocool. The mixture was diluted with methylene chloride and the insolubleswere removed by filtration. The solvent was removed from the filtrate byevaporation and the residue was purified by column chromatographyeluting with methylene chloride/methanol/aqueous ammonia (100/8/1). Thepurified product was triturated with ether collected by filtration anddried to give4-(4-chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline(230 mg, 53%).

¹H NMR Spectrum: (DMSOd₆) 1.18 (t, 3H); 2.02 (m, 2H); 2.48 (m, 2H); 3.94(s, 3H); 4.06 (q, 2H); 4.15 (t, 2H); 7.18 (s, 1H); 7.32 (m, 1H); 7.54(m, 2H); 7.78 (s, 1H); 8.34 (s, 1H); 9.52 (s, 1H)

MS-ESI: 434 [MH]⁺ Elemental analysis: Found C 58.0 H 4.8 N 9.8C₂₁H₂₁N₃O₄ClF Requires C 58.1 H 4.9 N 9.7%

A mixture of4-(4-chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline(220 mg, 0.5 mmol) in aqueous sodium hydroxide solution (4 ml of a 2Msolution, 8 mmol), water (2 ml) and methanol (0.5 ml) was stirred andheated at 40° C. for 3 hours. The mixture was allowed to cool and wasthen acidified with 2M hydrochloric acid. The resulting whiteprecipitate was collected by filtration and washed with acetone andwater to give7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(170 mg, 83%).

EXAMPLE 43

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg,0.75 mmol) was added to a mixture of7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(250 mg, 0.62 mmol), (prepared as described for the starting material inExample 42), 1-methylpiperazine (0.21 ml, 2.32 mmol) and4-dimethylaminopyridine (300 mg, 2.46 mol) in DMF (7.5 ml). The reactionmixture was stirred at ambient temperature for 24 hours and thevolatiles were removed by evaporation. Water was added to the residueand the aqueous mixture was extracted with methylene chloride (3×30 ml).The combined organic extracts were washed with brine and the solvent wasremoved by evaporation. The residue was triturated with ether and theprecipitate was collected by filtration. The solid was purified bycolumn chromatography eluting with methylene chloride/methanol/aqueousammonia (100/8/1). The purified product was triturated with ethercollected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline(133 mg, 44%).

m.p. 248-250° C.

¹H NMR Spectrum: (DMSOd₆) 2.00 (t, 2H); 2.15 (s, 3H); 2.25 (m, 4H); 2.45(m, 2H); 3.45 (m, 4H); 3.92 (s, 3H); 4.15 (t, 2H); 7.18 (s, 1H); 7.30(d, 1H); 7.55 (m, 2H); 7.78 (s, 1H); 8.34 (s, 1H); 9.52 (s, 1H)

MS-ESI: 488 [MH]⁺ Elemental analysis: Found C 58.6 H 5.5 N 13.9C₂₄H₂₇N₅O₃ClF0.2H₂O Requires C 58.6 H 5.6 N 14.3%

EXAMPLE 44

Oxalyl chloride (0.4 ml, 2.2 mmol) was added to a suspension of7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(260 mg, 0.64 mmol), (prepared as described for the starting material inExample 42), in methylene chloride (25 ml) followed by 1 drop of DMF.The mixture was stirred at ambient temperature for 2.5 hours and thevolatiles were removed by evaporation. A solution of pyrrolidine (0.13ml, 2.1 mmol) in N,N-dimethylacetamide (8 ml) was added to the solidresidue and the mixture was stirred at ambient temperature for 2 hours.The volatiles were removed by evaporation and the residue was purifiedby column chromatography eluting with methylenechloride/methanol/aqueous ammonia (100/8/1). The purified product wastriturated with acetone, collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylcarbonylpropoxy)quinazoline(206 mg, 70%).

m.p. 254-256° C.

¹H NMR Spectrum: (DMSOd₆) 1.76 (m, 2H); 1.85 (m, 2H); 2.02 (m, 2H); 2.41(t, 2H); 3.26 (t, 2H); 3.38 (t, 2H); 3.95 (s, 3H); 4.15 (t, 2H); 7.18(s, 1H); 7.32 (d, 1H); 7.55 (m, 2H); 7.78 (s, 1H); 8.34 (s, 1H); 9.52(s, 1H)

MS-ESI: 459 [MH]⁺ Elemental analysis: Found C 59.9 H 5.3 N 12.0C₂₃H₂₄N₄O₃ClF Requires C 60.2 H 5.3 N 12.2%

EXAMPLE 45

A mixture of4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline(210 mg, 0.52 mmol), water (5 ml) and TFA (5 ml) was stirred at ambienttemperature for 3 hours then heated at 60° C. for 1 hour. The solutionwas allowed to cool, then diluted with water and the resultingprecipitate was collected by filtration and dried. The solid wasdissolved in methanol (10 ml) and cyclopentylamine (0.057 ml, 0.57 mmol)and dried 3 Å molecular sieves (2.5 g) were added. The mixture wasstirred for 30 minutes, glacial acetic acid (0.20 ml, 3.2 mmol) andsodium cyanoborohydride (150 mg, 2.4 mmol) were added and the reactionstirred for 4 hours then left to stand for 18 hours. The insolubles wereremoved by filtration and the solvent was removed from the filtrate byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol/aqueous ammonia (100/8/1). The purifiedproduct was triturated with ether/hexane, collected by filtration anddried to give4-(4-chloro-2-fluoroanilino)-7-(2-cyclopentylaminoethoxy)-6-methoxyquinazoline(80 mg, 36%).

m.p. 171-173° C.

¹H NMR Spectrum: (DMSOd₆) 1.55 (m, 8H); 2.94 (t, 2H); 3.08 (m, 1H); 3.94(s, 3H); 4.19 (t, 2H); 7.19 (s, 1H); 7.33 (m, 1H); 7.52 (dd, 1H); 7.59(t, 1H); 7.78 (s, 1H); 8.34 (s, 1H); 9.50 (s, 1H)

MS-ESI: 431 [MH]⁺

The starting material was prepared as follows:

Bromoacetaldehyde dimethyl acetal (0.74 ml, 3.1 mmol) was added to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(10.0 g, 3.13 mmol), (prepared as described for the starting material inExample 2), and anhydrous potassium carbonate (2.16 g, 15.6 mmol) in DMF(30 ml). The mixture was stirred and heated at 110° C. for 4 hours, thenallowed to cool and the volatiles were removed by evaporation. Water wasadded to the residue and the aqueous mixture was extracted withmethylene chloride (×4). The extracts were combined, washed with brineand dried by filtration through phase separating paper. The volatileswere removed by evaporation, the residue was triturated with ether,collected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline(440 mg, 35%).

¹H NMR Spectrum: (DMSOd₆) 3.36 (s, 6H); 3.94 (s, 3H); 4.05 (d, 2H); 4.75(t, 1H); 7.22 (s, 1H); 7.32 (m, 1H); 7.52 (m, 1H); 7.58 (t, 1H); 7.80(s, 1H); 8.35 (s, 1H); 9.52 (s, 1H)

MS-ESI: 408 [MH]⁺

EXAMPLE 46

Diethyl azodicarboxylate (1.55 ml 9.89 mmol),4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3mmol), (prepared as described for the starting material in Example 48),and a solution of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (697 mg, 4.9mmol), (prepared as described for the starting material in Example 17),in methylene chloride (5 ml) were added successively to a solution oftriphenylphosphine (2.59 g, 9.89 mmol) in methylene chloride (150 ml)cooled at 5° C. The mixture was stirred at ambient temperature for 10minutes then methylene chloride (100 ml) was added followed successivelyby triphenylphosphine (432 mg, 1.6 mmol),(E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (232 mg, 1.6 mmol) and diethylazodicarboxylate (246 μl, 1.6 mmol). The mixture w stirred at ambienttemperature for 30 minutes and then the solvent was removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol (8/2 followed by 7/3 and 6/4). Thesemi-purified product was repurified by column chromatography elutingwith methylene chloride/methanol (8/2 followed by 7.5/2.5). The purifiedproduct was dissolved in methylene chloride, 3.7M ethereal hydrogenchloride (3 ml) was added and the volatiles were removed by evaporation.The residue was triturated with ether, collected by filtration and driedunder vacuum to give(E)-4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-ylbut-2-en-1-yloxy)quinazolinehydrochloride (600 mg, 32%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.8-1.9 (m, 2H); 2.0-2.1 (m, 2H);3.0-3.1 (m, 2H); 3.45-3.55 (m, 2H); 3.88 (d, 2H); 4.01 (s, 3H); 4.9 (d,2H); 6.0 (td, 1H); 6.3 (td, 1H); 7.41 (s, 1H); 7.5-7.65 (m, 2H); 7.82(d, 1H); 8.13 (s, 1H); 8.88 (s, 1H)

MS-(EI): 487 [M.]⁺ Elemental analysis: Found C 48.2 H 4.9 N 9.6C₂₃H₂₄N₄O₂BrF0.5H₂O2HCl Requires C 48.5 H 4.8 N 9.8%

EXAMPLE 47

Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(160 mg, 0.5 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (393 mg, 1.5 mmol) and1-(3-hydroxypropyl)-2-pyrrolidinone (107 mg, 0.75 mmol) in methylenechloride (5 ml) under nitrogen. The mixture was stirred for 20 minutesat ambient temperature and then purified by pouring directly onto acolumn of silica eluting with methylene chloride/ethyl acetate/methanol(60/35/5 followed by 60/30/10). The purified product was triturated withether and collected by filtration. The solid was dissolved in ethylacetate and treated with 3M hydrogen chloride in ethyl acetate (0.4 ml).The precipitate was collected by filtration, washed with ethyl acetateand dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazolinehydrochloride (170 mg, 70%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.9-2.0 (m, 2H); 2.0-2.1 (m, 2H);2.21 (t, 2H); 3.4-3.5 (m, 4H); 4.02 (s, 3H); 4.20 (s, 3H); 4.20 (t, 2H);7.32 (s, 1H); 7.46 (dd, 1H); 7.63 (t, 1H); 7.71 (dd, 1H); 8.17 (s, 1H);8.87 (s, 1H);

MS-ESI: 445 [MH]⁺ Elemental analysis: Found C 54.9 H 4.7 N 11.6C₂₂H₂₂N₄O₃ClF 0.3H₂O0.85HCl Requires C 54.9 H 4.9 N 11.6%

The starting material was prepared as follows:

A solution of γ-butyrolactone (8.6 g, 0.1 mol) and 3-amino-1-propanol (9g, 0.12 mol) was heated at reflux for 18 hours. The crude productmixture was distilled under reduced pressure to give1-(3-hydroxypropyl)-2-pyrrolidinone (2.5 g, 17%).

b.p.˜130° C. under ˜0.05 mmHg

¹H NMR Spectrum: (CDCl₃) 1.7-1.8 (m, 3H); 2.0-2.15 (m, 2H); 2.44 (t,2H); 3.4-3.5 (m, 4H); 3.54 (t, 2H)

MS-(EI): 143 [M]⁺

EXAMPLE 48

Using a method analogous to that in Example 47,4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.mmol) in methylene chloride (5 ml) was treated with1-(3-hydroxypropyl)-2-pyrrolidinone (86 mg, 0.6 mmol),triphenylphosphine (314 mg, 1.2 mmol) and diethyl azodicarboxylate (209mg, 1.2 mmol) and was purified and isolated to give4-(4-bromo-2-fluoroanilino)-4-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazolinehydrochloride (140 mg, 67%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.9-2.0 (m, 2H); 2.0-2.1 (m, 2H);2.21 (t, 2H); 3.4-3.5 (m, 4H); 4.02 (s, 3H); 4.20 (t, 2H); 7.32 (s, 1H);7.5-7.65 (m, 2H); 7.82 (d, 1H); 8.15 (s, 1H); 8.87 (s, 1H)

MS-ESI: 490 [MH]⁺ Elemental analysis: Found C 49.9 H 4.4 N 10.5C₂₂H₂₂N₄O₃BrF0.2H₂O0.95HCl Requires C 50.1 H 4.5 N 10.6%

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (8.35 g, 27.8mmol), (prepared as described for the starting material in Example 1),and 4-bromo-2-fluoroaniline (5.65 g, 29.7 mmol) in 2-propanol (200 ml)was heated at reflux for 4 hours. The resulting precipitate wascollected by filtration, washed with 2-propanol and then ether and driedunder vacuum to give7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (9.46 g, 78%).

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 4.0 (s, 3H); 5.37 (s, 2H); 7.35-7.5(m, 4H); 7.52-7.62 (m, 4H); 7.8 (d, 1H); 8.14 (9s, 1H); 8.79 (s, 1H)

MS-ESI: 456 [MH]⁺ Elemental analysis: Found C 54.0 H 3.7 N 8.7C₂₂H₁₇N₃O₂BrF0.9HCl Requires C 54.2 H 3.7 N 8.6%

A solution of7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (9.4 g, 19.1 mmol) in TFA (90 ml) was heated at reflux for50 minutes. The mixture was allowed to cool and was poured on to ice.The resulting precipitate was collected by filtration and dissolved inmethanol (70 ml). The solution was adjusted to pH9-10 with concentratedaqueous ammonia solution. The mixture was concentrated to half initialvolume by evaporation. The resulting precipitate was collected byfiltration, washed with water and then ether, and dried under vacuum togive 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5.66 g,82%).

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 3.95 (s, 3H); 7.09 (s, 1H); 7.48 (s,1H); 7.54 (t, 1H); 7.64 (d, 1H); 7.79 (s, 1H); 8.31 (s, 1H)

MS-ESI: 366 [MH]⁺ Elemental analysis: Found C 49.5 H 3.1 N 11.3C₁₅H₁₁N₃O₂BrF Requires C 49.5 H 3.0 N 11.5%

EXAMPLE 49

Methanesulphonyl chloride (32 mg, 0.275 mmol) was added dropwise to amixture of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline(109 mg, 0.25 mmol) and triethylamine (30 mg, 0.3 mmol) in methylenechloride (3 ml) cooled at 0° C. The solution was stirred for 2 hours at0° C. and the volatiles were removed by evaporation. The residue waspartitioned between ethyl acetate and water, the organic layer wasseparated, washed with brine, dried (MgSO₄) and the solvent removed byevaporation. The solid was triturated with ether and collected byfiltration. The solid was dissolved in methylene chloride containingmethanol (0.5 ml) and 3M hydrogen chloride in ethyl acetate (0.3 ml) wasadded. The suspension was diluted with ethyl acetate and concentrated byevaporation. The resulting solid product was collected by filtration,washed with ether and dried under vacuum to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-1N-methylsulphonyl]amino)propoxy)quinazolinehydrochloride (85 mg, 61%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.1-2.2 (m, 2H); 2.82 (s, 3H); 2.89(s, 3H); 3.29 (t, 2H); 4.02 (s, 3H); 4.27 (t, 2H); 7.35 (s, 1H);7.55-7.65 (m, 2H); 7.79 (d, 1H); 8.12 (s, 1H); 8.88 (s, 1H)

MS-(EI): 512 [M.]⁺ Elemental analysis: Found C 43.5 H 4.2 N 10.0C₂₀H₂₂N₄O₄BrFS0.6H₂O0.75HCl Re- C 43.5 H 4.4 N 10.2% quires

The starting material was prepared as follows:

Diethyl azodicarboxylate (522 mg, 3 mmol) was added dropwise to asuspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(364 mg, 1 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (786 mg, 3 mmol) and3-methylamino-1-propanol (178 mg, 2 mmol), (J. Am. Chem. Soc., 1954, 76,2789), in methylene chloride (4 ml) under nitrogen. The mixture wasstirred for 1 hour at ambient temperature, neutral alumina (˜20 g) wasadded to the reaction mixture and the solvent was removed byevaporation. The powder was poured onto a column of neutral alumina andwas eluted with a mixture of methylene chloride/methanol (95/5 followedby 90/10 and 80/20). The purified product was triturated with ether,collected by filtration, washed with ether and dried under vacuum togive4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline(220 mg, 50%).

EXAMPLE 50

A solution of diethyl azodicarboxylate (209 mg, 1.2 mmol) in methylenechloride (1 ml) and then(S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol) wasadded dropwise to a suspension of4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4mmol), (prepared as described for the starting material in Example 48),and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml)under nitrogen. The mixture was stirred for 1 hour at ambienttemperature and further triphenylphosphine (109 mg, 0.4 mmol) and(S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (40 mg, 0.23 mmol)were added followed by the dropwise addition of diethyl azodicarboxylate(70 mg, 0.4 mmol). The mixture was stirred for 30 minutes at ambienttemperature and further(S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (34 mg, 0.2 mmol) wasadded. The mixture was then stirred for 2 hours at ambient temperatureand the mixture was purified by pouring directly onto a column of silicaand eluting with methylene chloride/ethyl acetate/methanol (60/35/5).The purified product was triturated with ether, collected by filtration,washed with ether and dried under vacuum. The solid was dissolved inmethylene chloride and 3M hydrogen chloride in ethyl acetate (0.4 ml)was added. The resulting precipitate was collected by filtration, washedwith ethyl acetate and dried under vacuum to give(S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazolinehydrochloride (110 mg, 47%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD; 60° C.) 1.9-2.0 (m, 2H); 2.0-2.1 (m,2H); 2.15-2.25 (m, 2H); 3.2-3.3 (m, 1H); 3.3-3.5 (m, 2H); 3.7-3.8 (m,1H); 4.02 (s, 3H); 4.15-4.2 (m, 1H); 4.3-4.4 (m, 2H); 7.4 (s, 1H);7.5-7.6 (m, 2H); 7.75 (d, 1H); 8.2 (s, 1H); 8.83 (s, 1H)

MS-(EI): 518 [M.]⁺ Elemental analysis: Found C 46.0 H 4.9 N 11.2C₂₃H₂₅N₅O₃BrF 0.8H₂O1.9HCl Requires C 45.9 H 4.8 N 11.6%

The starting material was prepared as follows:

3-Bromo-1-propanol (584 mg, 4.2 mmol) was added to a mixtureof(S)-pyrrolidine-2-carboxamide (399 mg, 3.5 mmol) and potassiumcarbonate (966 mg, 7 mmol) in acetonitrile (10 ml). The mixture washeated at reflux for 5 hours and the mixture was stirred for 18 hours atambient temperature. The insolubles were removed by filtration and thesolvent was removed from the filtrate by evaporation. The residue waspurified by column chromatography on silica eluting with methylenechloride/methanol (9/1 followed by 8/2) to give(S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (365 mg, 60%).

MS-(EI): 173 [M.]⁺

EXAMPLE 51

Methoxyacetyl chloride (34 mg, 0.31 mmol) was added to a solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(113 mg, 0.3 mmol), (prepared as described for the starting material inExample 60), and triethylamine (33 mg, 0.33 mmol) in methylene chloride(3 ml). The mixture was stirred for 18 hours at ambient temperature andwas then partitioned between ethyl acetate and brine. The organic layerwas separated, dried (MgSO₄) and the solvent removed by evaporation. Theresidue was purified by chromatography on silica eluting with methylenechloride/acetonitrile/methanol (6/3/1). The purified solid product wastriturated with methylene chloride and ether, collected by filtration,washed with ether and dried under vacuum. The solid was dissolved in amixture of methylene chloride/methanol (1/1) and 2M hydrogen chloride inethyl acetate (0.5 ml) was added. The mixture was diluted with ether andand the resulting precipitate was collected by filtration, washed withether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl]amino)ethoxy)quinazolinehydrochloride (62 mg, 42%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD; 80° C.) 2.9-3.2 (br s, 3H); 3.35 (s,3H); 3.8-3.9 (br s, 2H); 4.05 (s, 3H); 4.0-4.3 (m, 2H); 4.4 (t, 2H); 7.4(s, 1H); 7.45 (d, 1H); 7.6-7.7 (m, 2H); 8.1 (s, 1H); 8.8 (s, 1H)

MS-ESI: 449 [MH]⁺ Elemental analysis: Found C 48.8 H 4.6 N 10.7C₂₁H₂₂N₄O₄ClF0.9H₂O1.35HCl Requires C 49.0 H 4.9 N 10.9%

EXAMPLE 52

Diethyl azodicarboxylate (400 mg, 2.3 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(250 mg, 0.78 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (615 mg, 2.3 mmol) and4-(2-hydroxyethyl)-3-morpholinone (170 mg, 1.17 mmol), (EP 580402A2), inmethylene chloride (5 ml) under nitrogen. The mixture was stirred for 4hours at ambient temperature, methylene chloride (5 ml) was added andstirring was continued for a further 18 hours at ambient temperature.THF (5 ml), 4-(2-hydroxyethyl)-3-morpholinone (113 mg, 0.78 mmol),triphenylphosphine (204 mg, 0.78 mmol) ere added and diethylazodicarboxylate (136 mg, 0.78 mmol) was then added dropwise. Themixture was stirred for 5 minutes at ambient temperature, and waspurified by pouring directly onto a silica column, eluting withmethylene chloride/ethyl acetate/methanol (5/4/1). The purified solidwas dissolved in methylene chloride and 2M methanolic hydrogen chloride(0.5 ml) was added. The mixture was concentrated by evaporation and thendiluted with ether. The resulting precipitate was collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-4-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazolinehydrochloride (150 mg, 39%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.6 (t, 2H); 3.8-3.9 (m, 4H); 4.05(s, 3H); 4.1 (s, 3H); 4.4 (t, 2H); 7.3 (s, 1H); 7.45 (d, 1H); 7.65 (t,1H); 7.7 (d, 1H); 8.1 (s, 1H); 8.9 (s, 1H)

MS-ESI: 469 [MNa]⁺ Elemental analysis: Found C 51.6 H 4.4 N 11.8C₂₁H₂₀N₄O₄ClF0.35H₂O0.95HCl Re- C 51.7 H 4.5 N 11.5% quires

EXAMPLE 53

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(128 mg, 0.4 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (314 mg, 1.2 mmol) and2-(2-morpholinoethoxy)ethanol (97 mg, 0.56 mmol) in methylene chloride(4 ml) under nitrogen. The mixture was stirred for 1 hour at ambienttemperature, triphenylphosphine (105 mg, 0.4 mmol),2-(2-morpholinoethoxy)ethanol (49 mg, 0.28 mmol) and diethylazodicarboxylate (70 mg, 0.4 mmol) were added. The mixture was stirredfor 1 hour at ambient temperature and was purified by pouring directlyonto a silica column eluting with methylenechloride/acetonitrile/methanol (6/3/1). The purified product wastriturated with ether, collected by filtration and dissolved inmethylene chloride. 2M Ethereal hydrogen chloride (0.5 ml) was added andthe resulting precipitate was collected by filtration, washed with etherand dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazolinehydrochloride (100 mg, 45%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.1-3.2 (m, 2H); 3.3-3.5 (m, 5H);3.7-3.8 (m, 2H); 3.9-4.0 (m, 5H); 4.02 (s, 3H); 4.4 (br s, 2H); 7.46 (s,1H); 7.48 (d, 1H); 7.6 (t, 1H); 7.7 (d, 1H); 8.25 (s, 1H); 8.89 (s, 1H)

MS-ESI: 477 [MH]⁺ Elemental analysis: Found C 48.8 H 5.6 N 9.9C₂₃H₂₆N₄O₄ClF1H₂O1.95HCl Requires C 48.8 H 5.3 N 9.9%

The starting material was prepared as follows:

2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a mixture ofmorpholine (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40 mmol) inacetonitrile (50 ml). The mixture was heated at reflux for 6 hours andthen stirred for 18 hours at ambient temperature. The insolubles wereremoved by filtration and the volatiles were removed from the filtrateby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol (95/5 followed by 90/10 andthen 80/20) to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).

¹H NMR Spectrum: (CDCl₃) 2.5 (br s, 4H); 2.59 (t, 2H); 3.6-3.85 (m, 10H)

MS-(EI): 175 [M.]⁺

EXAMPLE 54

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(128 mg, 0.4 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (314 mg, 1.2 mmol) and(S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol),(prepared as described for the starting material in Example 50), inmethylene chloride (4 ml). The mixture was stirred for 2 hours atambient temperature, and further triphenylphosphine (105 mg, 0.4 mmol)and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (49 mg, 0.28 mmol)were added followed by the dropwise addition of diethyl azodicarboxylate(70 mg, 0.4 mmol). The mixture was stirred for 1 hour at ambienttemperature, and was purified by pouring directly onto a silica columneluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by60/25/15). The purified oil was triturated with ether, collected byfiltration, washed with ether and dried under vacuum. The solid wasdissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5ml) was added. The mixture was diluted with ether and the resultingprecipitate was collected by filtration, washed with ether and driedunder vacuum to give(S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (70 mg, 32%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.8-2.0 (m, 2H); 2.05-2.15 (m, 2H);2.2-2.3 (m, 2H); 3.1-3.5 (m, 2H); 3.7-3.8 (m, 1H); 4.02 (s, 3H);4.05-4.2 (m, 2H); 4.3 (m, 2H); 7.04 (s, 1H); 7.45 (d, 1H); 7.65 (t, 1H);7.7 (d, 1H); 8.22 (s, 1H); 8.88 (s, 1H)

MS-ESI: 474 [MH]⁺ Elemental analysis: Found C 49.4 H 12.4 N 5.3C₂₃H₂₅N₅O₃ClF1.5H₂O1.55HCl Requires C 49.5 H 12.6 N 5.3%

EXAMPLE 55

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(128 mg, 0.4 mmol), (prepared as described for the starting material inExample 2), cis-3-(2,6-dimethylmorpholino)-1-propanol (97 mg, 0.56 mmol)and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml)under nitrogen. The mixture was stirred for 1 hour at ambienttemperature and the solvent was removed by evaporation. The residue waspurified by column chromatography eluting with methylenechloride/methanol (95/5 followed by 90/10). The purified product wasdissolved in methylene chloride and 2M ethereal hydrogen chloride (1 ml)was added. The solution was diluted with ether and left to stand. Theresulting precipitate was collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazolinehydrochloride (130 mg, 59%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.17 (d, 6H); 2.3-2.4 (m, 2H); 2.7(t, 2H); 3.25-3.35 (m, 2H); 3.55 (d, 2H); 3.94.0 (m, 2H); 4.03 (s, 3H);4.35 (t, 2H); 7.43 (s, 1H); 7.45 (d, 1H); 7.63 (t, 1H); 7.70 (d, 1H);8.25 (s, 1H); 8.88 (s, 1H)

MS-ESI: 475 [MH]⁺ Elemental analysis: Found C 51.7 H 6.0 N 9.7C₂₄H₂₈N₄O₃ClF0.6H₂O1.95HCl Requires C 51.8 H 5.6 N 10.0%

The starting material was prepared as follows:

3-Chloro-1-propanol (1.04 g, 11 mmol) followed by potassium carbonate(2.07 g, 15 mmol) was added to a solution of 2,6-dimethylmorpholine(1.15 g, 10 mmol), (supplied by Aldrich Chemical Company Limited as amixture of isomers), in acetonitrile (15 ml). The mixture was heated atreflux overnight and allowed to cool, the insolubles were removed byfiltration and the volatiles were removed from the filtrate byevaporation. The residue was purified by column chromatography on silicaeluting with methylene chloride/acetonitrile/methanol (60/35/5 followedby 60/30/10) to give cis-3-(2,6-dimethylmorpholino)-1-propanol (500 mg).

¹H NMR Spectrum: (CDCl₃) 1.16 (d, 6H); 1.7-1.8 (m, 4H); 2.61 (t, 2H);2.91 (d, 2H); 3.6-3.7 (m, 2H); 3.81 (t, 2H)

MS-ESI: 173 [M.]⁺

EXAMPLE 56

A solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline(180 mg, 0.4 mmol), (prepared as described for the starting material inExample 11), in anhydrous THF (2 ml) and benzene (2 ml) was purged ofoxygen and placed under nitrogen.Tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) followed bya solution of sodium triisopropylsilylthiolate (102 mg, 0.48 mmol),(Tetrahedron Lett. 1994, 35, 3221), in THF (2 ml) was added and themixture was heated at reflux for 2 hours. The mixture was allowed tocool to ambient temperature and 4-(3-chloropropyl)morpholine (98 mg, 0.6mmol), (J. Am. Chem. Soc. 1945, 67, 736), DMF (2 ml) andtetrabutylammonium fluoride (0.5 ml of a 1M solution in THF, 0.5 mmol)were added sequentially. The mixture was stirred for 1 hour at ambienttemperature, the volatiles were removed by evaporation and the residuewas partitioned between ethyl acetate and water. The organic layer wasseparated, washed with brine, dried (MgSO₄) and the solvent removed byevaporation. The residue was purified on neutral alumina eluting withmethylene chloride/acetone (90/10 followed by 80/20). The purifiedproduct was triturated in a mixture of ether and hexane, collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropylthio)quinazolinehydrochloride (65 mg, 30%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.1-2.2 (m, 2H); 3.1-3.2 (m, 2H);3.22 (t, 2H); 3.3-3.4 (m, 2H); 3.47 (d, 2H); 3.74 (t, 2H); 4.0 (d, 2H);4.08 (s, 3H); 7.48 (d, 1H); 7.64 (t, 2H); 7.68 (d, 1H); 7.86 (s, 1H);8.19 (s, 1H); 8.91 (s, 1H)

MS-ESI: 463 [MH]⁺ Elemental analysis: Found C 47.6 H 5.16 N 47.6C₂₂H₂₄N₄O₂ClFS1.2H₂O1.85HCl Requires C 47.8 H 5.16 N 47.8%

EXAMPLE 57

3-Chloroperbenzoic acid (188 mg, 1.05 mmol) was added in portions to asolution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethylthio)quinazoline(275 mg, 0.7 mmol), (prepared as described in Example 11), in methylenechloride (6 ml). The mixture was stirred for 30 minutes at ambienttemperature, diluted with methylene chloride (20 ml), washed withaqueous sodium hydrogen carbonate solution and then brine, dried (MgSO₄)and the solvent removed by evaporation. The residue was purified bycolumn chromatography eluting with methylene chloride/acetone (8/2followed by 7/3 and 6/4). The purified product was dissolved inmethylene chloride and 3M ethereal hydrogen chloride (0.5 ml) was added.The mixture was diluted with ether and the resulting precipitate wascollected by filtration, washed with ether and dried under vacuum togive 4-(4-chloro-2-fluoroanilino)-6-methoxy7-(2-methoxyethylsulphinyl)quinazoline hydrochloride (110 mg 38%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.05 (td, 1H); 3.24 (s, 3H); 3.5-3.6(m, 1H); 3.7-3.8 (m, 2H); 4.1 (s, 3H); 7.5 (d, 1H); 7.65 (t, 1H); 7.75(d, 1H); 8.2 (s, 1H); 8.4 (s, 1H); 9.0 (s, 1H)

MS-ESI: 410 [MH]⁺ Elemental analysis: Found C 47.9 H 4.2 N 9.3C₁₈H₁₇N₃O₃ClFS0.5H₂O0.85HCl Requires C 48.0 H 4.2 N 9.3%

EXAMPLE 58

Diethyl azodicarboxylate (218 mg, 1.25 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(159 mg, 0.5 mmol), (prepared as described for the starting material inExample 2), 4-hydroxy-1-methylpiperidine (115 mg, 1 mmol) andtriphenylphosphine (328 mg, 1.25 mmol) in methylene chloride (5 ml)cooled at 5° C. under nitrogen. The mixture was stirred for 1 hour atambient temperature, the solvent was removed by evaporation and theresidue was partitioned between 2M hydrochloric acid and ether. Theaqueous layer was separated, adjusted to pH9 with aqueous sodiumhydrogen carbonate solution and extracted with methylene chloride. Themethylene chloride layer was washed with brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified on neutralalumina eluting with methylene chloride/methanol (97/3). The purifiedproduct was triturated with ether, collected by filtration and dried togive4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline(180 mg, 79%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.9-2.0 (m, 1H); 2.05-2.15 (m, 2H);2.35-2.45 (m, 1H); 2.85 and 2.90 (2s, 3H); 3.05-3.25 (m, 2H); 3.45 (m,1H); 3.6 (d, 1H); 4.1 and 4.12 (2s, 3H); 4.8-4.9 (m, 0.5H); 5-5.05 (m,0.5H); 7.4-7.7 (m, 4H); 8.2 (d, 1H); 8.9 (s, 1H)

MS-ESI: 417 [MH]⁺

EXAMPLE 59

Methanesulphonyl chloride (35 μl, 0.46 mmol) was added dropwise to asolution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline(170 mg, 0.43 mmol) and triethylamine (67 μl, 0.48 mmol) in methylenechloride (3 ml). The mixture was stirred for 5 hours at ambienttemperature, the volatiles was removed by evaporation and the residuewas partitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and then brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography on silica eluting with methylenechloride/acetonitrile/methanol (70/28/2). The purified product wasdissolved in a mixture of methylene chloride/methanol (1/1) and 2Methereal hydrogen chloride (1 ml) was added. The volatiles were removedby evaporation and the residue was triturated with ether, collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)quinazolinehydrochloride (133 mg, 61%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.1-2.2 (m, 2H); 2.82 (s, 3H); 2.89(s, 3H); 3.3 (t, 2H); 4.02 (s, 3H); 4.27 (t, 2H); 7.36 (s, 1H); 7.46 (d,1H); 7.6-7.7 (m, 2H); 8.14 (s, 1H); 8.88 (s, 1H)

MS-ESI: 469 [MH]⁺ Elemental analysis: Found C 48.1 H 4.7 N 10.8C₂₀H₂₂N₄O₄ClFS0.9HCl Requires C 47.9 H 4.6 N 11.2%

The starting material was prepared as follows:

A solution of di-tert-butyl dicarbonate (4.9 g, 22 mmol) in THF (12 ml)was added dropwise to a solution of 3-methylamino-1-propanol (2 g, 22mmol), (J. Am. Chem. Soc., 1954, 76, 2789), in a mixture of THF (12 ml)and water (12 ml). The mixture was stirred for 18 hours at ambienttemperature, the THF was removed by evaporation. The aqueous residue wasextracted with ether. The extracts were combined, washed with 0.1Mhydrochloric acid, and then brine, dried (MgSO₄) and the solvent removedby evaporation to give3-([N-(tert-butylcarbonyl)-N-methyl]amino)-N-propanol (3.95 g, 95%).

¹H NMR Spectrum: (CDCl₃) 1.46 (s, 9H); 1.6-1.8 (m, 2H); 2.83 (s, 3H);3.3-3.4 (br s, 2H); 3.5-3.6 (br s, 2H)

MS-(EI): 190 [MH]⁺

Diethyl azodicarboxylate (2.4 ml, 15 mmol) was added dropwise to asolution of 3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol (1.77g, 9.4 mmol),4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2 g, 6.26mmol), (prepared as described for the starting material in Example 2),and triphenylphosphine (4.1 g, 15 mmol) in methylene chloride (50 ml)under nitrogen. The mixture was stirred for 1 hour at ambienttemperature, and further3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol (236 mg, 1.2mmol), triphenylphosphine (820 mg, 3.1 mmol) and diethylazodicarboxylate (492 μl, 3.1 mmol) were added. The solution was stirredfor 1 hour at ambient temperature and concentrated by evaporation. Theresidue was purified on column chromatography eluting with acetonitrile.The purified product was triturated with ether, collected by filtrationand repurified by column chromatography eluting with methylenechloride/methanol (97/3) to give7-(3-([N-(tert-butylcarbonyl)-N-methyl]amino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(2.2 g, 72%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.3 (s, 9H); 2.0-2.1 (m, 2H); 2.8-2.9(br s, 3H); 3.4-3.5 (m, 2H); 4.0 (s, 3H); 4.25 (t, 2H); 7.3 (s, 1H);7.45 (d, 1H); 7.6-7.7 (m, 2H); 8.08 (s, 1H); 8.88 (s, 1H)

MS-(EI): 491 [MH]⁺ Elemental analysis: Found C 58.6 H 5.8 N 11.3C₂₄H₂₈N₄O₄ClF Requires C 58.7 H 5.7 N 11.4%

A solution of7-(3-([N-(tert-butylcarbonyl)-N-methyl]amino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(2.1 g, 4.3 mmol) in a mixture of methylene chloride (6 ml) and TFA (5ml) was stirred at ambient temperature for 1 hour. Toluene was added andthe volatiles were removed by evaporation. The residue was dissolved inwater and the solution was adjusted to pH7-8 with saturated aqueoussodium hydrogen carbonate solution. The resulting precipitate wasseparated by centrifugation and decanting the filtrate and the solidproduct was thoroughly washed with water. The solid was recrystallisedfrom methylene chloride/methanol, the product collected by filtration,washed with water, and then ether and dried under vacuum over phosphoruspentoxide to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline(1.4 g, 83%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.2-2.3 (m, 2H); 2.65 (s, 3H);3.1-3.2 (m, 2H); 4.05 (s, 3H); 4.32 (t, 2H); 7.37 (s, 1H); 7.48 (d, 1H);7.64 (t, 1H); 7.67 (d, 1H); 8.11 (s, 1H); 8.9 (s, 1H)

MS-(EI): 391 [MH]⁺

EXAMPLE 60

Triethylamine (44 μL, 0.32 mmol) and then a solution of 2-bromoethylmethyl ether (40 mg, 0.29 mmol) in acetone (0.5 ml) was added dropwiseto a solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(100 mg, 0.26 mmol) in acetone (2.5 ml) heated at 50° C. under nitrogen.The mixture was stirred for 7 hours at 50° C. the mixture was allowed tocool and partitioned between ethyl acetate and water. The organic layerwas separated, washed with brine, dried (MgSO₄) and the volatilesremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (92/8). Thepurified product was dissolved in methylene chloride, insolubles wereremoved by filtration and 2.2M ethereal hydrogen chloride (0.5 ml) wasadded to the filtrate. The volatiles were removed by evaporation and theresidue was triturated with ether, collected by filtration and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-(2-methoxyethyl)-N-methyl]amino)ethoxy)quinazolinehydrochloride (22 mg, 16%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.0 (s, 3H); 3.35 (s, 3H); 3.4-3.6(m, 2H); 3.65-3.85 (m, 4H); 4.03 (s, 3H); 4.64 (t, 2H); 7.45 (s, 1H);7.47 (d, 1H); 7.63 (t, 1H); 7.69 (d, 1H); 8.23 (s, 1H); 8.9 (s, 1H)

MS-ESI: 435 [MH]⁺ Elemental analysis: Found C 48.9 H 5.3 N 10.4C₂₁H₂₄N₄O₃ClF0.8H₂O1.85HCl Requires C 48.8 H 5.3 N 10.8%

The starting material was prepared as follows:

Diethyl azodicarboxylate (3.13 g, 24 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2.56 mg, 8mmol), (prepared as described for the starting material in Example 2),2-([N-(tert-butylcarbonyl)-N-methyl]amino)ethanol (2.1 g, 1.2 mmol),(Synth. Commun. 1993, 23, 2443), and triphenylphosphine (6.3 g, 24 mmol)in methylene chloride (50 ml) under nitrogen. The mixture was stirredfor 1.5 hours at ambient temperature and further2-([N-(tert-butylcarbonyl)-N-methyl]amino)ethanol (0.21 g, 1.2 mmol),triphenylphosphine (630 mg, 2.4 mmol) and diethyl azodicarboxylate (0.31g, 2.4 mmol) were added. The mixture was stirred for 1 hour; the mixturewas purified by pouring it directly onto a silica column and elutingwith methylene chloride/ether/methanol (60/30/10) to give7-(2-([N-(tert-butylcarbonyl)-N-methyl]amino)ethoxy)-N-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(3.8 g, 99%).

A solution of7-(2-([N-(tert-butylcarbonyl)-N-methyl]amino)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(2.38 g, 5 mmol) in methylene chloride (5 ml) and TFA (10 ml) wasstirred at ambient temperature for 1 hour. Toluene was added and thevolatiles were removed by evaporation. The residue was partitionedbetween 2M hydrochloric acid and ethyl acetate. The aqueous layer wasadjusted to pH8 with sodium hydrogen carbonate and extracted with ethylacetate. The organic extracts were combined, washed with brine, dried(MgSO₄) and the solvent removed by evaporation to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(700 mg, 37%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.75 (s, 3H); 3.5-3.6 (m, 2H); 4.05(s, 3H); 4.5 (t, 2H); 7.4 (s, 1H); 7.4-7.5 (m, 1H); 7.65 (t, 1H); 7.7(d, 1H); 8.15 (s, 1H); 8.8 (s, 1H)

EXAMPLE 61

Dimethylcarbamyl chloride (38 μl, 0.42 mmol) was added to a solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(150 mg, 0.4 mmol), (prepared as described for the starting material inExample 60), and triethylamine (61 μl, 0.44 mmol) in methylene chloride(4 ml). The mixture was stirred for 2.5 hours at ambient temperature,the resulting precipitate was collected by filtration and washed withether. The solid was purified by column chromatography, eluting withmethylene chloride/methanol (92/8). The purified product was dissolvedin methylene chloride/methanol (1/1), 2.9M ethereal hydrogen chloride (1ml) was added and the volatiles were removed by evaporation. The residuewas triturated with ether and the solid product collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N′,N′,N-trimethylureido)ethoxy)quinazolinehydrochloride (80 mg, 41%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.73 (s, 6H); 2.91 (s, 3H); 3.59 (t,2H); 4.0 (s, 3H); 4.34 (t, 2H); 7.36 (s, 1H); 7.5 (d, 1H); 7.63 (t, 1H);7.68 (d, 1H); 8.1 (s, 1H); 8.9 (s, 1H)

MS-(EI): 447 [M.]⁺ Elemental analysis: Found C 51.2 H 5.1 N 13.9C₂₁H₂₃N₅O₃ClF0.5H₂O1HCl Requires C 51.1 H 5.1 N 14.2%

EXAMPLE 62

7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150mg, 0.35 mmol) and 1-acetylpiperazine (135 mg, 1 mmol) were heatedtogether at 140° C. for 10 minutes. The mixture was allowed to cool andwas dissolved in a mixture of methylene chloride/ethyl acetate. Thesolution was washed with water, and then brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (9/1). Thepurified product was dissolved in methylene chloride and 2.9M etherealhydrogen chloride was added. The precipitate was collected byfiltration, washed with ether and dried under vacuum to give7-(2-(4-acetylpiperazin-1-yl)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (152 mg, 79%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD; 50° C.) 2.07 (s, 3H); 3.3-3.7 (br s,8H); 3.75 (t, 2H); 4.05 (s, 3H); 4.65 (t, 2H); 7.45 (br s, 2H); 7.6-7.7(m, 2H); 8.15 (s, 1H); 8.9 (s, 1H)

MS-(EI): 473 [M.]⁺ Elemental analysis: Found C 49.8 H 5.0 N 12.5C₂₃H₂₅N₅O₃ClF0.5H₂O1.9HCl Requires C 50.0 H 5.1 N 12.7%

The starting material was prepared as follows:

1,2-Dibromoethane (5.4 ml, 62 mmol) was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5 g, 15.6mmol), (prepared as described for the starting material in Example 2),and potassium carbonate (8.6 g, 62 mmol) in DMF (50 ml) and the mixturestirred for 18 hours at ambient temperature. Water was added and theresulting precipitate was collected by filtration. The solid waspurified by chromatography on neutral alumina eluting with methylenechloride/methanol (95/5). The semi-purified product was repurified bychromatography on silica eluting with methylene chloride/methanol(97/3). The purified product was triturated with ether, collected byfiltration, washed with ether and dried under vacuum to give7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(3.58 g, 54%).

¹H NMR Spectrum: (DMSOd₆) 3.28 (s, 3H); 3.96 (s, 3H); 4.48 (t, 2H); 4.85(t, 2H); 7.21 (s, 1H); 7.34 (d, 1H); 7.5-7.6 (m, 2H); 7.80 (s, 1H); 8.36(s, 1H); 9.55 (s, 1H)

EXAMPLE 63

A mixture of7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(150 mg, 0.32 mmol) in 1-methylpiperazine (2 ml) was heated at 100° C.for 1 hour. The mixture was allowed to cool and was partitioned betweenethyl acetate and water. The organic layer was separated and washed withwater and then brine, dried (MgSO₄) and the solvent removed byevaporation. The residue was purified by column chromatography on silicaeluting with methylene chloride/methanol (85/15 followed by 80/20). Thepurified solid product was dissolved in methylene chloride/methanol(1/1) and 2.9M ethereal hydrogen chloride was added. The volatiles wereremoved by evaporation and the solid was triturated with ether,collected by filtration, washed with ether and dried under vacuum togive 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin1-yl]ethoxy)ethoxy)quinazoline hydrochloride (54 mg, 28%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD; 50° C.) 2.9 (s, 3H); 3.5-3.8 (m,10H); 3.95 (br s, 4H); 4.03 (s, 3H); 4.4 (m, 2H); 7.40-7.45 (m, 1H);7.42 (s, 1H); 7.55-7.65 (m, 2H); 8.15 (s, 1H); 8.8 (s, 1H)

MS-ESI: 490 [MH]⁺ Elemental analysis: Found C 46.0 H 5.6 N 10.9C₂₄H₂₉N₅O₃ClF1.5H₂O2.9HCl Requires C 46.3 H 5.6 N 11.2%

The starting material was prepared as follows:

2-Bromoethyl ether (1.57 ml, 12 mmol) was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.1mmol), (prepared as described for the starting material in Example 2),and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml). The mixturewas stirred for 18 hours at ambient temperature and was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water and then brine, dried (MgSO₄) and the solvent removed byevaporation. The residue was purified by column chromatography on silicaeluting with methylene chloride/acetonitrile/methanol (60/38/2). Thepurified product was triturated with ether, collected by filtration,washed with ether and dried under vacuum to give7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(763 mg, 52%).

¹H NMR Spectrum: (CDCl₃) 3.5 (t, 2H); 3.9 (t, 2H); 3.95 (t, 2H); 4.03(s, 3H); 4.35 (t, 2H); 7.03 (s, 1H); 7.2-7.4 (m, 4H); 8.55 (t, 1H); 8.7(s, 1H)

MS-ESI: 472 [MH]⁺

EXAMPLE 64

A solution of7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(150 mg, 0.32 mmol), (prepared as described for the starting material inExample 63), in pyrrolidine (2 ml) was heated at 80° C. for 5 hours. Themixture was allowed to cool and was partitioned between ethyl acetateand water. The organic layer was washed with water and then brine, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography on silica eluting with methylenechloride/methanol/triethylamine (80/20/0 followed by 80/20/1). Thepurified product was dissolved in methylene chloride and 2.9M etherealhydrogen chloride (1 ml) was added. The volatiles were removed byevaporation, the residue was triturated with ether, collected byfiltration and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazolinehydrochloride (35 mg, 20%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.8-1.9 (m, 2H); 1.95-2.1 (m, 2H);3.05-3.15 (m, 2H); 3.45 (t, 2H); 3.55-3.65 (m, 2 μl); 3.8-3.85 (m, 2H);3.95-4.0 (m, 2H); 4.01 (s, 3H); 4.4 (br s, 2H); 7.39 (s, 1H); 7.48 (d,1H); 7.65 (t, 1H); 7.7 (d, 1H); 8.11 (s, 1H); 8.89 (s, 1H)

MS-ESI: 461 [MH]⁺ Elemental analysis: Found C 49.4 H 5.4 N 10.1C₂₃H₂₆N₄O₃ClF1.2H₂O2HCl Requires C 49.7 H 5.5 N 10.1%

EXAMPLE 65

1-(2-(2-Bromoethyl)ethoxy)-2-pyrrolidinone (272 mg, 1.1 mmol) was addedto a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg,0.78 mmol), (prepared as described for the starting material in Example2), and potassium carbonate (324 mg, 2.3 mmol) in DMF (5 ml) and themixture stirred for 4 hours at ambient temperature. The mixture waspartitioned between ethyl acetate and water, the organic layer wasseparated, washed with water and then brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography on alumina eluting with methylenechloride/acetonitrile/methanol (60/37/3). The semi-purified product wasrepurified by column chromatography on silica eluting with methylenechloride/methanol (95/5). The purified product was dissolved inmethylene chloride and 2.9M ethereal hydrogen chloride (1 ml) was added.The volatiles were removed by evaporation, the residue was trituratedwith ether, collected by filtration, washed with ether and dried undervacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[2-oxopyrrolidin-1-yl]ethoxy)ethoxy)quinazolinehydrochloride (63 mg, 16%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.85-1.95 (m, 2H); 2.2 (t, 2H);3.35-3.45 (m, 4H); 3.65 (t, 2H); 3.9 (br s, 2H); 4.02 (s, 3H); 4.35 (brs, 2H); 7.35 (s, 1H); 7.45 (d, 1H); 7.65 (t, 1H); 7.7 (d, 1H); 8.15 (s,1H); 8.88 (s, 1H)

MS-ESI: 475 [MH]⁺ Elemental analysis: Found C 53.2 H 5.0 N 11.1C₂₃H₂₄N₄O₄ClF0.6H₂O0.85HCl Requires C 53.5 H 5.1 N 10.8%

The starting material was prepared as follows:

A solution of 2-pyrrolidinone (1.5 g, 17.6 mmol) in anhydrous toluene (8ml) was added dropwise to a suspension of sodium hydride (741 mg, 18mmol, prewashed with pentane) in anhydrous toluene (60 ml) and themixture was stirred at 100° C. for 1.5 hours. The mixture was allowed tocool to ambient temperature and tetrabutylammonium bromide (57 mg, 0.176mmol) was added followed by 2-bromoethyl ether (8 ml, 35 mmol). Themixture was stirred for 21 hours at ambient temperature, the insolubleswere removed by filtration and the solid was washed with ether. Thevolatiles were removed from the filtrate by evaporation and the residuewas purified by column chromatography on silica eluting with methylenechloride/acetonitrile/methanol (60/38/2) to give1-(2-(2-bromoethyl)ethoxy)2-pyrrolidinone (971 mg, 23%).

¹H NMR Spectrum: (CDCl₃) 2.0-2.1 (m, 2H); 2.4 (t, 2H); 3.4-3.5 (m, 4H);3.52 (t, 2H); 3.65 (t, 1H); 3.78 (t, 2H)

MS-(EI): 237 [M]⁺

EXAMPLE 66

Diethyl azodicarboxylate (325 μl, 2 mmol) was added dropwise to amixture of (E)-4-morpholinobut-2-en-1-ol (151 mg, 0.96 mmol), (J. Med.Chem. 1972, 15, 110-112),4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (220 mg,0.688 mol), (prepared as described for the starting material in Example2), and triphenylphosphine (541 mg, 2 mmol) in methylene chloride (4ml). The mixture was stirred for 30 minutes at ambient temperature, andfurther (E)-4-morpholinobut-2-en-1-ol (10 mg, 0.06 mmol),triphenylphosphine (36 mg, 0.137 mol) and diethyl azodicarboxylate (22μl, 0.14 mmol) were added. The mixture was stirred for 20 minutes andthe volatiles were removed by evaporation. The residue was purified bycolumn chromatography on silica eluting with methylene chloride/methanol(92/8). The purified solid was dissolved in methylene chloride and 2Methereal hydrogen chloride (3 ml) was added. The volatiles were removedby evaporation and the solid was triturated with ether, collected byfiltration, washed with ether and dried under vacuum to give(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazolinehydrochloride (165 mg, 45%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.1-3.15 (m, 2H); 3.35-3.45 (m, 2H);3.75 (t, 2H); 3.9 (d, 2H); 4.0 (d, 2H); 4.03 (s, 3H); 4.95 (d, 2H); 6.05(td, 1H); 6.3 (td, 1H); 7.45 (s, 1H); 7.47 (d, 1H); 7.62 (t, 1H); 7.7(d, 1H); 8.25 (s, 1H); 8.88 (s, 1H)

MS-ESI: 459 [MH]⁺ Elemental analysis: Found C 50.3 H 5.3 N 10.1C₂₃H₂₄N₄O₃ClF1.4H₂O1.8HCl Requires C 50.2 H 5.2 N 10.2%

EXAMPLE 67

Diethyl azodicarboxylate (368 μl, 2.34 mmol) was added dropwise to amixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(284 mg, 0.78 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (613 mg, 2.34 mmol) and4-(2-hydroxyethyl)-3-morpholinone (170 mg, 1.17 mmol), (EP580402A2), inmethylene chloride (10 ml) under nitrogen. The mixture was stirred for2.5 hours at ambient temperature, the insolubles were removed byfiltration. The filtrate was purified by pouring it directly on to acolumn of silica and eluting with methylene chloride/ethylacetate/methanol (60/35/5). The purified product was triturated withether and collected by filtration. The solid was dissolved in methylenechloride containing a few drops of methanol and 3.8M ethereal hydrogenchloride (0.5 ml) was added. The volatiles were removed by evaporationand the residue was triturated with ether, collected by filtration anddried under vacuum to give of4-(4-bromo-2-fuoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazolinehydrochloride (108 mg, 26%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.56 (t, 2H); 3.8-3.9 (m, 4H); 4.06(s, 3H); 4.06 (s, 2H); 4.4 (t, 2H); 7.35 (s, 1H); 7.5-7.6 (m, 2H); 7.8(d, 1H); 8.13 (s, 1H); 8.87 (s, 1H)

MS-ESI: 491 [MH]⁺ Elemental analysis: Found C 47.1 H 4.1 N 10.5C₂₁H₂₀N₄O₄BrF 0.3H₂O 0.95HCl Re- C 47.5 H 4.1 N 10.5% quires

EXAMPLE 68

Diethyl azodicarboxylate (283 μl, 1.8 mmol) was added dropwise to amixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(218 mg, 0.6 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (95 μl, 0.84 mmol) and1-(2-hydroxyethyl)-2-pyrrolidinone (95 μl, 0.84 mmol) in methylenechloride (8 ml) under nitrogen. The mixture was stirred for 4 hours atambient temperature, and then purified by pouring it directly on to acolumn of silica and eluting with methylenechloride/acetonitrile/methanol (60/32.5/7.5). The purified product wastriturated with ether and collected by filtration. The solid wasdissolved in methylene chloride/methanol (1/1) and 2M ethereal hydrogenchloride (1 ml) was added. The volatiles were removed by evaporation,the residue was triturated with ether, collected by filtration and driedunder vacuum to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazolinehydrochloride (182 mg, 60%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.9-2.0 (m, 2H); 2.24 (t, 2H); 3.53(t, 2H); 3.7 (t, 2H); 4.01 (s, 3H); 4.34 (t, 2H); 7.36 (s, 1H); 7.5-7.6(m, 2H); 7.75 (d, 1H); 8.16 (s, 1H); 8.87 (s, 1H)

MS-ESI: 477 [MH]⁺ Elemental analysis: Found C 50.2 H 4.3 N 10.9C₂₁H₂₀N₄O₃BrF 0.8HCl Requires C 50.0 H 4.2 N 11.1%

EXAMPLE 69

Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to amixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(182 mg, 0.5 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (393 mg, 1.5 mmol) and2-(2-methoxyethoxy)ethanol (84 μl, 0.7 mmol) in methylene chloride (7ml) under nitrogen. The mixture was stirred for 4 hours at ambienttemperature, the reaction mixture was purified by pouring it directly onto a column of silica and eluting with ethyl acetate/petroleum ether(9/1 followed by 10/0). The purified product was triturated with etherand collected by filtration. The solid was dissolved in methylenechloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added.The mixture was concentrated by evaporation and the precipitate wascollected by filtration, washed with ether and dried under vacuum togive4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazolinehydrochloride (84 mg, 34%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.26 (s, 3H); 3.47 (m, 2H); 3.64 (m,2H); 3.85 (m, 2H); 4.02 (s, 3H); 4.35 (m, 2H); 7.35 (s, 1H); 7.5-7.7 (m,2H); 7.82 (d, 1H); 8.12 (s, 1H); 8.87 (s, 1H)

MS-ESI: 468 [MH]⁺ Elemental analysis: Found C 47.5 H 4.4 N 8.7C₂₀H₂₁N₃O₄BrF0.65H₂O 0.65HCl Requires C 47.9 H 4.6 N 8.3%

EXAMPLE 70

Diethyl azodicarboxylate (567 μl, 3.6 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(383 mg, 1.2 mmol), (prepared as described for the starting material inExample 2), 4-(3-hydroxypropyl)-3,5-dioxomorpholine (291 mg, 1.68 mmol)and triphenylphosphine (944 mg, 3.6 mmol) in methylene chloride (10 ml)under nitrogen. The mixture was stirred at ambient temperature for 6hours and the insolubles were removed by filtration. The filtrate waspurified by pouring it directly on to a column of silica and elutingwith methylene chloride/acetonitrile/methanol (60/34/6 followed by60/24/16 and 60/16/24). The semi-purified product was repurified bycolumn chromatography eluting with methylenechloride/acetonitrile/methanol (5/4/1). The purified product wasdissolved in methylene chloride/methanol, 2M ethereal hydrogen chloride(1 ml) was added and the volatiles were removed by evaporation. Theresidue was triturated with ether, collected by filtration, washed withether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(3-(3,5-dioxomorpholino)propoxy)-6-methoxyquinazolinehydrochloride (56 mg, 10%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.0-2.1 (m, 2H); 3.35 (t, 2H); 3.98(s, 2H); 4.01 (s, 3H); 4.24 (t, 2H); 7.33 (s, 1H); 7.45 (d, 1H); 7.62(t, 1H); 7.68 (d, 1H); 8.13 (s, 1H); 8.87 (s, 1H)

MS-ESI: 475 [MH]⁺ Elemental analysis: Found C 48.9 H 4.4 C₂₂H₂₀N₄O₅ClF1.4H₂O 1HCl Requires C 49.2 H 4.5

The starting material was prepared as follows:

A solution of diglycolic anhydride (2.32 g, 20 mmol) in3-amino-1-propanol (6 ml) was refluxed at 180° C. for 3 hours. Thevolatiles were removed by evaporation and the residue was purified bycolumn chromatography on silica eluting with methylene chloride/methanol(8/2) to give 4-(3-hydroxypropyl)-3,5-dioxomorpholine (3.46 g, 99%).

¹H NMR Spectrum: (CDCl₃) 2.75-2.8 (m, 2H); 3.1 (br s, 1H); 3.45-3.5 (m,2H); 3.75 (t, 2H); 4.04 (s, 2H)

MS-(EI): 174 [MH]⁺

EXAMPLE 71

Diethyl azodicarboxylate (472 μl, 3 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(319.5 mg, 1 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (786 mg, 3 mmol) and4-(2-hydroxyethyl)-3,5-dioxomorpholine (223 mg, 1.4 mmol) in methylenechloride (10 ml) under nitrogen. The mixture was stirred at ambienttemperature for 4.5 hours and the insolubles were removed by filtration.The solvent was removed from the filtrate by evaporation and the residuewas purified by column chromatography eluting with methylenechloride/acetonitrile/methanol (85/12.5/2.5). The purified product wasdissolved in methylene chloride, 2M ethereal hydrogen chloride (1 ml)was added and the mixture was diluted with ether. The resultingprecipitate was collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dioxomorpholino)ethoxy)-6-methoxyquinazolinehydrochloride (97 mg, 20%).

¹H NMR (DMSOd₆; CF₃COOD) 4.0 (s, 3H); 4.19 (d, 2H); 4.39 (t, 2H); 4.45(s, 4H); 7.35 (s, 1H); 7.45 (d, 1H); 7.67 (t, 1H); 7.69 (d, 1H); 8.12(s, 1H); 8.87 (s, 1H)

MS-ESI: 461 [MH]⁺ Elemental analysis: Found C 49.9 H 3.9 N 11.1C₂₁H₁₈N₄O₅ClF 0.5H₂O 0.9HCl Requires C 50.2 H 4.0 N 11.1%

The starting material was prepared as follows:

Ethanolamine (2.44 g, 40 mmol) was added dropwise to a solution ofdiglycolic anhydride (2.32 g, 20 mmol) in pyridine (10 ml). The mixturewas stirred for 5 minutes at ambient temperature and then heated atreflux for 2 hours. The volatiles were removed by evaporation and theresidue was heated at 180° C. for 2 hours. The reaction mixture wasallowed to cool and was purified by column chromatography eluting withmethylene chloride/methanol (9/1) to give4-(2-hydroxyethyl)-3,5-dioxomorpholine (400 mg, 12.5%)

¹H NMR Spectrum: (CDCl₃) 1.6 (br s, 1H); 3.8 (t, 2H); 4.05 (t, 2H); 4.4(s, 4H)

MS-EI: 160 [MH]⁺

EXAMPLE 72

Diethyl azodicarboxylate (378 μl, 2.4 mmol) was added dropwise to amixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(292 mg, 0.8 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (629 mg, 2.4 mmol) and2-(2-morpholinoethoxy)ethanol (196 mg, 1.12 mmol), (prepared asdescribed for the starting material in Example 53), in methylenechloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hoursat ambient temperature and the mixture was purified by pouring itdirectly on to a column of silica and eluting with methylenechloride/acetonitrile/methanol (6/3/1). The purified product wasdissolved in methylene chloride/methanol and the insolubles were removedby filtration. 2M Ethereal hydrogen chloride (1 ml) was added to thefiltrate and the volatiles were removed by evaporation. The residue wastriturated with ether, collected by filtration, washed with ether anddried under vacuum to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazolinehydrochloride (232 mg, 49%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.1-3.2 (m, 2H); 3.35-3.4 (br s, 2H);3.45 (d, 2H); 3.75 (t, 2H); 3.9-4.0 (m, 6H); 4.02 (s, 3H); 4.4 (br s,2H); 7.45 (s, 1H); 7.5-7.6 (m, 2H); 7.8 (m, 1H); 8.22 (s, 1H); 8.87 (s,1H)

MS-ESI: 523 [MH]⁺ Elemental analysis: Found C 46.3 H 4.9 N 9.2C₂₃H₂₆N₄O₄BrF 0.5H₂O 1.8HCl Requires C 46.3 H 4.9 N 9.4%

EXAMPLE 73

Diethyl azodicarboxylate (2201 μl, 1.4 mmol) was added dropwise to amixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(170 mg, 0.46 mmol), (prepared as described for the starting material inExample 48), triphenylphosphine (367 mg, 1.4 mmol) and3-(1,1-dioxothiomorpholino)-1-propanol (135 mg, 0.7 mmol) in methylenechloride (4 ml) under nitrogen. The mixture was stirred for 1 hour atambient temperature and further triphenylphosphine (61 mg, 0.23 mmol),3-(1,1-dioxothiomorpholino)-1-propanol (30 mg, 0.23 mmol) and diethylazodicarboxylate (37 μl, 0.23 mmol) were added. The mixture was stirredfor 1 hour at ambient temperature and the mixture was purified bypouring it on to a column of silica and eluting with methylenechloride/methanol (95/5). The purified product was dissolved inmethylene chloride/methanol, 2.2M ethereal hydrogen chloride (1 ml) wasadded and the volatiles were removed by evaporation. The residue wastriturated with ether, collected by filtration, washed with ether anddried under vacuum to give4-(4-bromo-2-fluoroanilino)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazolinehydrochloride (138 mg, 47%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.3-2.4 (m, 2H); 3.5 (t, 2H); 3.7-3.8(br s, 4H); 3.85 (br s, 4H); 4.03 (s, 3H); 4.35 (t, 2H); 7.4 (s, 1H);7.5-7.6 (m, 2H); 7.8 (d, 1H); 8.21 (s, 1H); 8.88 (s, 1H)

MS-ESI: 539 [MH]⁺ Elemental analysis: Found C 42.1 H 4.6 N 8.6C₂₂H₂₄N₄O₄BrFS 1.1H₂O 1.85HCl Requires C 42.2 H 4.5 N 8.9%

The starting material was prepared as follows:

A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinyl sulphone (1g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture wasallowed to cool and was purified by column chromatography eluting withmethylene chloride/methanol (95/5) to give3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).

¹H NMR Spectrum: (CDCl₃) 1.7-1.8 (m, 2H); 2.73 (t, 2H); 3.06 (br s, 8H);3.25 (s, 1H); 3.78 (t, 2H)

MS-ESI: 194 [MH]⁺

EXAMPLE 74

A solution of 2-methoxyethylsulphonyl chloride (42 mg, 0.26 mmol), (J.Amer. Chem. Soc. 1992, 114, 1743-1749), in acetonitrile (1 ml) was addedto a mixture of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(94 mg, 0.25 mmol), (prepared as described for the starting material inExample 60), and triethylamine (80 μl, 0.5 mmol) in acetonitrile (15ml). The mixture was stirred for 10 minutes at ambient temperature, thevolatiles were removed by evaporation and the residue was partitionedbetween methylene chloride and water. The organic layer was separated,washed with brine, dried (MgSO₄) and the solvent removed by evaporation.The residue was purified by column chromatography eluting with methylenechloride/methanol (97/3). The purified product was dissolved inmethylene chloride (5 ml) and 2.2M ethereal hydrogen chloride (2 ml) wasadded and the volatiles were removed by evaporation. The residue wastriturated with ether, collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(2-([N-methyl-N-(2-methoxyethylsulphonyl)]amino)ethoxy)-6-methoxyquinazolinehydrochloride (86 mg, 64%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.96 (s, 3H); 3.28 (s, 3H); 3.47 (t,2H); 3.6-3.7 (m, 4H); 4.02 (s, 3H); 4.37 (t, 2H); 7.37 (s, 1H); 7.46 (d,1H); 7.64 (t, 1H); 7.7 (d, 1H); 8.15 (s, 1H); 8.88 (s, 1H)

MS-ESI 499 [MH]⁺ Elemental analysis: Found C 47.2 H 4.9 N 10.2C₂₁H₂₄N₄O₅ClFS 1HCl Requires C 47.1 H 4.7 N 10.5%

EXAMPLE 75

Using a method analogous to that in Example 74, a mixture of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline(102 mg, 0.27 mmol), (prepared as described for the starting material inExample 60), and triethylamine (0.1 ml, 0.72 mmol) in acetonitrile (17ml) was treated with 3-morpholinopropylsulphonyl chloride (75 mg, 0.28mmol), (WO 930181), to give, after purification and hydrochloride saltformation,4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-(3-morpholinopropylsulphonyl)]amino)ethoxy)quinazolinehydrochloride (96 mg, 54%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.1-2.2 (m, 2H); 3.0 (s, 3H);3.05-3.15 (m, 2H); 3.2-3.3 (m, 2H); 3.3-3.4 (m, 2H); 3.45 (d, 2H);3.65-3.8 (m, 4H); 3.95 (d, 2H); 4.03 (s, 3H); 4.39 (t, 2H); 7.42 (s,1H); 7.45 (d, 1H); 7.65 (t, 1H); 7.7 (d, 1H); 8.2 (s, 1H); 8.9 (s, 1H)

MS-ESI: 568 [MH]⁺

EXAMPLE 76

Diethyl azodicarboxylate (0.18 ml, 1.14 mmol) was added dropwise to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(111 mg, 0.35 mmol), (prepared as described for the starting material inExample 2), triphenylphosphine (312 mg, 1.19 mmol) and(S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (84 mg,0.42 mmol) in methylene chloride (10 ml) cooled at 0° C. under nitrogen.The mixture was stirred for 15 minutes at 0° C., the mixture was allowedto warm to ambient temperature and was then stirred for 22 hours.Further (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (10mg, 0.05 mmol), triphenylphosphine (35 mg, 0.13 mmol) and diethylazodicarboxylate (20 μl, 0.13 mmol) were added and the mixture wasstirred for a further 2 hours. The mixture was partitioned between waterand methylene chloride and the aqueous phase was adjusted to pH2 with 2Mhydrochloric acid. The aqueous layer was separated, adjusted to pH9 withsodium hydrogen carbonate and was extracted with methylene chloride. Thecombined organic extracts were washed with water and then brine, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography on silica eluting with methylenechloride/methanol (85/15 followed by 75/25 and 60/40). The purifiedproduct was dissolved in methylene chloride (5 ml) and methanol (1 ml),3.9M ethereal hydrogen chloride (0.5 ml) was added and the mixture wasdiluted with ether. The resulting precipitate was collected byfiltration, washed with ether, and dried under vacuum to give(S)-4-(4-chloro-2-fuoroanilino)-7-(3-(2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolinehydrochloride (86 mg, 32%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.8-1.95 (m, 2H); 2.1-2.3 (m, 4H);2.92 (s, 3H); 3.0 (s, 3H); 3.2-3.45 (m, 3H); 3.75-3.85 (m, 1H); 4.0 (s,3H); 4.32 (t, 2H); 4.75 (t, 1H); 7.4 (s, 1H); 7.45 (d, 1H); 7.65 (t,1H); 7.7 (d, 1H); 8.25 (s, 1H); 8.9 (s, 1H)

MS-ESI: 502 [MH]⁺ Elemental analysis: Found C 50.2 H 5.5 N 11.6C₂₃H₂₉N₅O₃ClF 1H₂O 2HCl Requires C 50.6 H 5.6 N 11.8%

The starting material was prepared as follows:

A mixture of (S)-2-(N,N-dimethylcarbamoyl)pyrrolidine (426 mg, 3 mmol),(Chem. pharm. Bull. 1973, 21, 2112-2116), 3-bromo-1-propanol (0.41 ml,4.5 mmol) and potassium carbonate (829 mg, 6 mmol) in acetonitrile (6ml) was heated at reflux for 8 hours. The mixture was allowed to cooland was partitioned between methylene chloride and water. The organiclayer was separated, washed with brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography, eluting with methylene chloride/methanol (a gradientfrom 90/10 to 60/40) to give(S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (290 mg,48%).

¹H NMR Spectrum: (CDCl₃; CD₃COOD) 1.8-2.1 (m, 4H); 2.2-2.3 (m, 1H);2.6-2.7 (m, 1H); 3.0 (s, 3H); 3.10 (s, 3H); 3.4-3.6 (m, 3H); 3.75-3.85(m, 3H); 5.05 (m, 1H)

MS-ESI: 223 [MNa]′

EXAMPLE 77

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesiumstearate 1.5 (e) Injection I (50 mg/ml) Compound X 5.0% w/v 1N Sodiumhydroxide solution 15.0% v/v 0.1N Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II 10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1N Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g)InjectioN III (1 mg/ml.buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%NoteThe above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

1-16. (canceled)
 17. A method for producing an anti-cancer effect in awarm-blooded animal in need of such treatment which comprisesadministering to said animal an effective amount of a quinazolinederivative of formula I:

wherein: m is an integer from 1 to 2; R¹ represents hydrogen, hydroxy,halogeno, nitro, trifluoromethyl, cyano, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkylthio, or —NR⁵R⁶ (wherein R⁵ and R⁶, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl); R² representshydrogen, hydroxy, halogeno, methoxy, amino or nitro; R³ representshydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino or nitro; X¹ represents —O—; R⁴ isselected from one of the following twelve groups: 1) C₁₋₅alkylR¹²(wherein R¹² is a 5 or 6 membered saturated heterocyclic group with oneor two heteroatoms, selected independently from O, S and N, whichheterocyclic group is linked to C₁₋₅alkyl through a carbon atom andwhich heterocyclic group may bear one or two substituents selected fromoxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl) or C₁₋₅alkylR¹³ (wherein R¹³ is a group selectedfrom pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which groupmay bear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 2)C₂₋₅alkenylR¹⁴ (wherein R¹⁴ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl); 3) C₂₋₅alkynylR¹⁵ (wherein R¹⁵ is a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which heterocyclic group maybear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 4)C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶ (wherein X² and X³ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR¹⁷CO—, —CONR¹⁸—, —SO₂NR¹⁹—,—NR²⁰SO₂— or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹⁶ represents hydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be—CH₂— when R⁴ is C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶; 5) C₁₋₅alkylX⁴COR²² (whereinX⁴ represents —O— or —NR²³— (wherein R²³ represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents —NR²⁴R²⁵ or —OR²⁶ (whereinR²⁴, R²⁵ and R²⁶ which may be the same or different each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 6) C₁₋₅alkylX⁵R²⁷ (whereinX⁵ represents —O—, —S—, —SO—, —SO₂—, —OCO—, —NR²⁸CO—, —CONR²⁹, —SO₂R³⁰—,—NR³¹SO₂— or —NR³²— (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) orX⁵ is carbonyl, and R²⁷ represents cyclopentyl, cyclohexyl or a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when R²⁷ isC₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³⁰— or —NR³¹SO₂— and X¹ is not—CH₂—); 7) C₁₋₃alkoxyC₂₋₄alkyl provided that X¹ is —S—, —SO— or —SO₂—;8) C₁₋₅alkylX⁶C₁₋₅alkylR³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,—NR³⁴CO—, —CONR³⁵—, —SO₂NR³⁶—, —NR³⁷SO₂— or —NR³⁸— (wherein R³⁴, R³⁵,R³⁶, R³⁷ and R³⁸ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ represents cyclopentyl, cyclohexyl or a 5or 6 membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl); 9) R³⁹ (wherein R³⁹ is a group selected frompyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 10)C₁₋₅alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least onesubstituent selected from C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,C₁₋₄hydroxyalkyl and —CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each independentlyrepresents hydrogen or C₁₋₄alkyl); 11) C₁₋₅alkylR⁴³ (wherein R⁴³ ismorpholino which may bear one or two substituents selected from oxo,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) withthe proviso that when R⁴ is C₁₋₅alkylR⁴³, X¹ is —S—, —SO—, —SO₂—,—SO₂NR⁹— or —NR¹⁰SO₂—; and 12) C₁₋₅alkylR⁴⁴ (wherein R⁴⁴ is morpholinowhich bears at least one and optionally two substituents selected fromoxo, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); or apharmaceutically acceptable salt thereof.
 18. A method for inhibitingthe effects of VEGF in a warm-blooded animal in need of such treatmentwhich comprises administering to said animal an effective inhibitingamount of a quinazoline derivative of formula I:

wherein: m is an integer from 1 to 2; R¹ represents hydrogen, hydroxy,halogeno, nitro, trifluoromethyl, cyano, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkylthio, or —NR R (wherein R⁵ and R⁶, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl); R² representshydrogen, hydroxy, halogeno, methoxy, amino or nitro; R³ representshydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino or nitro; X¹ represents —O—; R⁴ isselected from one of the following twelve groups: 1) C₁₋₅alkylR¹²(wherein R¹² is a 5 or 6 membered saturated heterocyclic group with oneor two heteroatoms, selected independently from O, S and N, whichheterocyclic group is linked to C₁₋₅alkyl through a carbon atom andwhich heterocyclic group may bear one or two substituents selected fromoxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl) or C₁₋₅alkylR³ (wherein R¹³ is a group selectedfrom pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which groupmay bear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 2)C₂₋₅alkenylR¹⁴ (wherein R¹⁴ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl); 3) C₂₋₅alkynylR¹⁵ (wherein R¹⁵ is a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which heterocyclic group maybear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 4)C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶ (wherein X² and X³ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR¹⁷CO—, —CONR¹⁸—, —SO₂NR¹⁹—,—NR²SO₂— or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹⁶ represents hydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be—CH₂— when R⁴ is C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶; 5) C₁₋₅alkylX⁴COR²² (whereinX⁴ represents —O— or —NR²³— (wherein R²³ represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents —NR²⁴R²⁵ or —OR²⁶ (whereinR²⁴, R²⁵ and R²⁶ which may be the same or different each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 6) C₁₋₅alkylX⁵R²⁷ (whereinX⁵ represents —O—, —S—, —SO—, —SO₂—, —OCO—, —NR²⁸CO—, —CONR²⁹—,—SO₂NR³⁰—, —NR³¹SO₂— or —NR³²— (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) orX⁵ is carbonyl, and R²⁷ represents cyclopentyl, cyclohexyl or a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when R²⁷ isC₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³⁰— or —NR³¹SO₂— and X¹ is not—CH₂—); 7) C₁₋₃alkoxyC₂₋₄alkyl provided that X¹ is —S—, —SO— or —SO₂—;8) C₁₋₅alkylX⁶C₁₋₅alkylR³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,—NR³⁴CO—, CONR³⁵—, —SO₂NR⁶, NR³⁷SO₂— or —NR³⁸— (wherein R³⁴, R₃₅, R³⁶,R³⁷ and R³⁸ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ represents cyclopentyl, cyclohexyl or a 5or 6 membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl); 9) R³⁹ (wherein R³⁹ is a group selected frompyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 10)C₁₋₅alkyl⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least onesubstituent selected from C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,C₁₋₄hydroxyalkyl and —CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each independentlyrepresents hydrogen or C₁₋₄alkyl); 11) C₁₋₅alkylR⁴³ (wherein R⁴³ ismorpholino which may bear one or two substituents selected from oxo,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) withthe proviso that when R⁴ is C₁₋₅alkylR⁴³, X¹ is —S—, —SO—, —SO₂—,—SO₂NR⁹— or —NR¹⁰SO₂—; and 12) C₁₋₅alkylR⁴⁴ (wherein R⁴⁴ is morpholinowhich bears at least one and optionally two substituents selected fromoxo, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); or apharmaceutically salt thereof.
 19. A method for inhibiting the effectsof VEGF and EGF in a warm-blooded animal in need of such treatment whichcomprises administering to said animal an effective inhibiting amount ofa quinazoline derivative of formula I as claimed in claim 18 or apharmaceutically acceptable salt thereof.
 20. A method for inhibitingthe growth of a solid tumour of the colon, breast, prostate, lung orskin in a warm-blooded animal in need of such treatment which comprisesadministering to said animal an effective inhibiting amount of aquinazoline derivative of formula I:

wherein: m is an integer from 1 to 2; R¹ represents hydrogen, hydroxy,halogeno, nitro, trifluoromethyl, cyano, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkylthio, or —NR⁵R⁶ (wherein R⁵ and R⁶, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl); R² representshydrogen, hydroxy, halogeno, methoxy, amino or nitro; R³ representshydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino or nitro; X¹ represents —O—; R⁴ isselected from one of the following twelve groups: 1) C₁₋₅alkylR¹²(wherein R¹² is a 5 or 6 membered saturated heterocyclic group with oneor two heteroatoms, selected independently from O, S and N, whichheterocyclic group is linked to C₁₋₅alkyl through a carbon atom andwhich heterocyclic group may bear one or two substituents selected fromoxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl) or C₁₋₅alkylR¹³ (wherein R¹³ is a group selectedfrom pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which groupmay bear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 2)C₂₋₅alkenylR¹⁴ (wherein R¹⁴ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,carbamoyl, C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyland C₁₋₄alkoxycarbonyl); 3) C₂₋₅alkynylR¹⁵ (wherein R¹⁵ is a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which heterocyclic group maybear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 4)C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶ (wherein X² and X³ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR¹⁷CO—, —CONR¹⁸—, —SO₂NR¹⁹—,—NR²SO₂— or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹⁶ represents hydrogen or C₁₋₃alkyl) with the proviso that X¹ cannot be—CH₂— when R⁴ is C₁₋₅alkylX²C₁₋₅alkylX³R¹⁶; 5) C₁₋₅alkylX⁴COR²² (whereinX⁴ represents —O— or —NR²³— (wherein R²³ represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents —NR²⁴R²⁵ or —OR²⁶ (whereinR²⁴, R²⁵ and R²⁶ which may be the same or different each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 6) C₁₋₅alkylX⁵R²⁷ (whereinX⁵ represents —O—, —S—, —SO—, —SO₂—, —OCO—, —NR²³CO—, —CONR²¹—,—SO₂NR³¹, —NR³¹SO₂— or —NR³²— (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) orX⁵ is carbonyl, and R²⁷ represents cyclopentyl, cyclohexyl or a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl or R²⁷ is C₁₋₃alkyl with the proviso that when R²⁷ isC₁₋₃alkyl, X⁵ is —S—, —SO—, —SO₂—, —SO₂NR³⁰ or —NR³¹SO₂— and X¹ is not—CH₂—); 7) C₁₋₃alkoxyC₂₋₄alkyl provided that X¹ is —S—, —SO— or —SO₂—;8) C₁₋₅alkylX⁶C₁₋₅alkylR³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,—NR³⁴CO—, CONR³⁵, SO₂NR³⁶—, NR³⁷SO₂— or —NR³⁸— (wherein R³⁴, R³, R³⁶,R³⁷ and R³ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ represents cyclopentyl, cyclohexyl or a 5or 6 membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which cyclopentyl, cyclohexyl orheterocyclic group may bear one or two substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl,C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl andC₁₋₄alkoxycarbonyl); 9) R³⁹ (wherein R³⁹ is a group selected frompyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); 10)C₁₋₅alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least onesubstituent selected from C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,C₁₋₄hydroxyalkyl and —CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each independentlyrepresents hydrogen or C₁₋₄alkyl); 11) C₁₋₅alkylR⁴³ (wherein R⁴³ ismorpholino which may bear one or two substituents selected from oxo,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl) withthe proviso that when R⁴ is C₁₋₅alkylR⁴³, X¹ is —S—, —SO—, —SO₂—,—SO₂NR⁹— or —NR¹⁰SO₂—; and 12) C₁₋₅alkylR⁴⁴ (wherein R⁴⁴ is morpholinowhich bears at least one and optionally two substituents selected fromoxo, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, carbamoyl, C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, C₁₋₄alkanoyl and C₁₋₄alkoxycarbonyl); or apharmaceutically acceptable salt thereof.
 21. The method according toclaim 20 wherein the tumour is of the colon.
 22. The method according toclaim 20 wherein the tumour is of the lung.